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Lavie, Muriel, Benjamin Seunes, Philippe Prior, and Christian Boucher. "Distribution and Sequence Analysis of a Family of Type III-Dependent Effectors Correlate with the Phylogeny of Ralstonia solanacearum Strains." Molecular Plant-Microbe Interactions® 17, no. 8 (August 2004): 931–40. http://dx.doi.org/10.1094/mpmi.2004.17.8.931.
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In Ralstonia solanacearum, we previously have reported on the characterization of popP1 and popP2 genes. These genes encode type III-dependent pathogenicity effectors related to the large family of AvrRxv/YopJ cysteine prote-ases that are shared among pathogens of plants and animals. In this study, we identify a third gene, named popP3, that is inactivated in the genome sequence of strain GMI1000 by insertion of a copy of the insertion sequence ISRso13. The three popP genes are localized on two large chromosomal pathogenicity islands, with popP1 and popP2 being present on the same island. Phylogenic analysis demonstrated that the PopP2 and PopP3 proteins are clearly distinct from other effectors of this family previously characterized in plant and animal pathogens. Analysis of the distribution and allelic variations of the three genes in 30 strains representative of the biodiversity of R. solanacearum established that popP genes are distributed widely among strains from two of the three phyla previously defined on the basis of the structure of the core genome. Sequencing of the popP genes from the different strains revealed limited allelic variations at the three loci but did not show evidence of recombination between the popP genes. Limited allelic variation together with occurrence of insertion sequences within or in the close vicinity of popP genes and the presence of gene duplications in these pathogenicity islands suggest that genomic rearrangements might be a major evolutionary driving force controlling evolution of the genes encoded in these regions. The implications of these observations in terms of bacterial evolution, gene acquisition, and horizontal gene transfers are discussed.
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Sepúlveda, Carlos, Oscar Montiel, José M. Cornejo Bravo, and Roberto Sepúlveda. "Fuzzy Evaluation of Pharmacokinetic Models." Computational Intelligence and Neuroscience 2018 (November 1, 2018): 1–10. http://dx.doi.org/10.1155/2018/1983897.
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Population pharmacokinetic (PopPK) models allow researchers to predict and analyze drug behavior in a population of individuals and to quantify the different sources of variability among these individuals. In the development of PopPK models, the most frequently used method is the nonlinear mixed effect model (NLME). However, once the PopPK model has been developed, it is necessary to determine if the selected model is the best one of the developed models during the population pharmacokinetic study, and this sometimes becomes a multiple criteria decision making (MCDM) problem, and frequently, researchers use statistical evaluation criteria to choose the final PopPK model. The used evaluation criteria mentioned above entail big problems since the selection of the best model becomes susceptible to the human error mainly by misinterpretation of the results. To solve the previous problems, we introduce the development of a software robot that can automate the task of selecting the best PopPK model considering the knowledge of human expertise. The software robot is a fuzzy expert system that provides a method to systematically perform evaluations on a set of candidate PopPK models of commonly used statistical criteria. The presented results strengthen our hypothesis that the software robot can be successfully used to evaluate PopPK models ensuring the selection of the best PopPK model.
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Zuo, Fenghua, Jun Li, and Xiaoyong Sun. "Exploring Population Pharmacokinetic Modeling with Resampling Visualization." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/585687.
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Background. In the last decade, population pharmacokinetic (PopPK) modeling has spread its influence in the whole process of drug research and development. While targeting the construction of the dose-concentration of a drug based on a population of patients, it shows great flexibility in dealing with sparse samplings and unbalanced designs. The resampling approach has been considered an important statistical tool to assist in PopPK model validation by measuring the uncertainty of parameter estimates and evaluating the influence of individuals.Methods. The current work describes a graphical diagnostic approach for PopPK models by visualizing resampling statistics, such as case deletion and bootstrap. To examine resampling statistics, we adapted visual methods from multivariate analysis, parallel coordinate plots, and multidimensional scaling.Results. Multiple models were fitted, the information of parameter estimates and diagnostics were extracted, and the results were visualized. With careful scaling, the dependencies between different statistics are revealed. Using typical examples, the approach proved to have great capacity to identify influential outliers from the statistical perspective, which deserves special attention in a dosing regimen.Discussion. By combining static graphics with interactive graphics, we are able to explore the multidimensional data from an integrated and systematic perspective. Complementary to current approaches, our proposed method provides a new way for PopPK modeling analysis.
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Borghorst, Stephan, Rob Pieters, Hans Juergen Kuehnel, Joachim Boos, and Georg Hempel. "Population Pharmacokinetic of Native Escherichia Coli Asparaginase." Blood 114, no. 22 (November 20, 2009): 4803. http://dx.doi.org/10.1182/blood.v114.22.4803.4803.
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Abstract Abstract 4803 Introduction Native Escherichia Coli Asparaginase (ASNase) is an integral component in the therapy of acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma (NHL). There is a great interindividual variability in treatment intensity in patients treated with the same dose of ASNase. Population pharmacokinetics (PopPK) provides the possibility to divide the overall variability of a population in an inter- and intraindividual element and to develop more precise dosing recommendations. Furthermore, pharmacokinetic parameters can be estimated as well as possible covariates that may influence the pharmacokinetics of the drug can be identified. Patients and Methods The model building dataset consisted of 16 patients (233 samples) receiving 5000 U/m2 ASNase (Asparaginase Medac®) 8 times according to the DCOG-ALL 10 treatment protocol. Asparaginase activity was measured in a randomized clinical Phase 2 study comparing the pharmacokinetic and pharmacodynamic of a newly developed recombinant ASNase with that of the established ASNase (Asparaginase Medac®)[R. Pieters et al. Blood. 2008 Dec 15. 112(13):4832-8]. The PopPK-model was developed using NONMEM (version VI) with First Order Conditional Estimation (FOCE) method and INTERACTION option. Results A linear 2-compartmental model with a combined proportional (0.9%) and additive (48.1U/l) error model described the data adequately. The pharmacokinetic parameters estimated were: Total systemic clearance 0.135 ± 12.8% l/h/70kg, volume of distribution of the central compartment 4.27 ± 13.1% l/70kg, volume of distribution in the peripheral compartment 0.83 ± 80.4% l/70kg and intercompartmental clearance 0.058 l/h/70kg (mean ± interindividual variability). Body weight was identified as the most important covariate. Validity of the model was verified by simulating different dosages of ASNase (2500U/m2 and 10000U/m2) in induction and reinduction of the ALL-BFM treatment protocol. The median and mean ASNase activity was compared with published data [E. Ahlke et al. Br J Haematol. 1997 Mar. 96(4):675-81 and Boos et al. Eur J Cancer. 1996 Aug. 32A(9):1544-50]. Furthermore pharmacokinetic data obtained by a noncompartmental analysis [R. Pieters et al. Blood. 2008 Dec 15.112(13):4832-8] were compared with the pharmacokinetic data estimated by the PopPK model. Both procedures indicated on face validity of the PopPK model. Conclusion This PopPK analysis provides the first step in the development of a PopPK model for ASNase. Face validity of the PopPK model could be demonstrated and will be confirmed with an independent dataset. Disclosures: Pieters: Medac GmbH: Research Funding. Kuehnel:Medac GmbH: Employment. Boos:Medac GmbH: Honoraria. Hempel:Medac GmbH: Honoraria.
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Song, Ling, Cheng Cui, Ying Zhou, Zhongqi Dong, Zhiheng Yu, Yifan Xu, Tianyan Zhou, et al. "Toward Greater Insights on Applications of Modeling and Simulation in Pregnancy." Current Drug Metabolism 21, no. 9 (December 14, 2020): 722–41. http://dx.doi.org/10.2174/1389200221666200907143941.
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Pregnant women are often excluded from routine clinical trials. Consequently, appropriate dosing regimens for majority of drugs are unknown in this population, which may lead to unexpected safety issue or insufficient efficacy in this un-studied population. Establishing evidence through the conduct of clinical studies in pregnancy is still a challenge. In recent decades, physiologically-based pharmacokinetic (PBPK) modeling has proven to be useful to support dose selection under various clinical scenarios, such as renal and/or liver impairment, drug-drug interactions, and extrapolation from adult to children. By integrating gestational-dependent physiological characteristics and drug-specific information, PBPK models can be used to predict PK during pregnancy. Population pharmacokinetic (PopPK) modeling approach also could complement pregnancy clinical studies by its ability to analyze sparse sampling data. In the past five years, PBPK and PopPK approaches for pregnancy have made significant progress. We reviewed recent progress, challenges and potential solutions for the application of PBPK, PopPK, and exposure-response analysis in clinical drug development for pregnancy.
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Li, Anning, Shuangmin Ji, Weihua Yue, Hao Yan, Fang Dong, Canjun Ruan, Wenbiao Li, Wei Lu, Dai Zhang, and Chuanyue Wang. "Development of a population pharmacokinetic model of olanzapine for Chinese health volunteers and patients with schizophrenia." BMJ Open 8, no. 8 (August 2018): e020070. http://dx.doi.org/10.1136/bmjopen-2017-020070.
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ObjectiveOlanzapine is an atypical antipsychotic drug commonly used for the treatment of schizophrenia. However, there are still many complications associated with the use of olanzapine, and researchers continually strive to improve the handling of data from regular therapeutic drug monitoring (TDM). The objective of this study is to optimise the individualised treatment of olanzapine by establishing a population pharmacokinetics (PopPK) model in Chinese patients with schizophrenia.MethodsThis study integrates an extensive collection of concentration data from healthy volunteers after a single dose and a less extensive collection of samples from patients undergoing TDM. A PopPK model was developed using non-linear mixed-effects modelling. Potential covariates, including the olanzapine manufacturer and patient gender and age, were assessed during model development. A total of 616 plasma concentration levels from 22 healthy male individuals in China and 458 concentration levels from 112 male and 122 female patients with schizophrenia undergoing TDM at 12 hospitals in China were included in the analysis. The concentration profile could be best described using a two-compartment model with first-order absorption and elimination.ResultsThe absorption rate (Ka) of olanzapine ranged from 2.85 h–1to 5.39 h–1for the different formulations. The typical absorption time delay was 0.877 hour. Body weight had a considerable effect on the apparent volume of the centre compartment and showed a power relationship.ConclusionsA PopPK model of olanzapine in Chinese patients with schizophrenia was developed in this study. After determining the PK parameters of olanzapine, the results suggested that body weight exhibited a considerable impact effect on VC/F. The impact of subjects and formulations requires further study. The PopPK model established in this study is likely to provide some information for the individualised therapy of olanzapine.Trial registration numberChiCTR-TRC-10000934; Results.
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Wang, Z., B. Verstockt, S. Vermeire, J. Sabino, M. Ferrante, P. Declerck, and E. Dreesen. "P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S335—S336. http://dx.doi.org/10.1093/ecco-jcc/jjab076.431.
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Abstract Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.
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Stroh, Mark, Rachel Li, Hong Lu, Russ Wada, Jennifer Hope Richardson, John W. Frye, and Amy C. Peterson. "Preliminary clinical pharmacokinetics and dose-response to support a phase II dose selection for CX-2009: A masked probody drug conjugate to CD166." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3599. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3599.
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3599 Background: PROBODY therapeutics are antibody prodrugs with cleavable peptide masks designed to reduce off-tumor, on-target toxicities. The mask blocks binding in the periphery and is removed by tumor-associated proteases resulting in intratumoral binding. CX-2009 is a PROBODY drug conjugate directed against CD166/ALCAM, which is a target overexpressed in carcinomas but not suitable for traditional ADC targeting because it is expressed in normal epithelium. CX-2009 is conjugated to DM4, a potent microtubule inhibitor. Here we report preliminary clinical pharmacokinetic (PK) and exploratory dose-response (DR) analyses for CX-2009 from the ongoing phase 1/2 PROCLAIM-CX-2009 study (NCT03149549). Methods: Human PK and anti-drug antibody (ADA) data were obtained at selected times post-dose following IV 0.25–10 mpk CX-2009 Q3W and of 6 mpk Q2W. Covariates were selected for population PK (POPPK) based on multivariate screening at P< 0.01. Preliminary exploratory DR analyses were conducted for selected endpoints including adverse events of special interest and response data (CR, PR, SD, and PD). Results: Preliminary CX-2009 PK data from 92 subjects were available as of October 2019. Median free DM4 levels circulated at ≤0.3% of Total CX-2009 (masked + activated CX-2009) levels across the 1–10 mpk dose levels. A two-compartment POPPK model with linear elimination was fit to the Intact (masked form) CX-2009 data. The preliminary CX-2009 POPPK model estimates for Intact CX-2009 clearance (CL), volume of distribution, and half-life were 0.47 L/day, 4.51 L, and 7.14 days, respectively, with 91% of CX-2009 circulating as Intact CX-2009. ADA was not a statistically significant covariate on Intact CX-2009 CL. Evidence of clinical activity was observed at doses of 4 mpk Q3W or higher. DR analysis suggested that the frequency of grade ≥3 ocular toxicity events increased significantly at dose equivalents ≥8 mpk Q3W. POPPK simulations suggested that the targeted 90 nM trough concentration (based on nonclinical data) would be contained within the 90% prediction interval of predicted Intact CX-2009 levels following CX-2009 7 mpk. Conclusions: Preliminary CX-2009 PK data following CX-2009 0.25-10 mpk suggest that CX-2009 circulates predominantly as Intact CX-2009, and that Intact CX-2009 PK is not strongly influenced by target-mediated drug disposition or ADA. Preliminary DR and POPPK simulations support further evaluation of 7 mpk CX-2009 Q3W in selected cohort expansions. Clinical trial information: NCT03149549 .
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Stroh, Mark, Michelle Green, Bjorn L. Millard, William Garner, Hong Lu, Jennifer Hope Richardson, and Alison L. Hannah. "Preliminary population pharmacokinetics supports phase II dose selection for masked anti-PD-L1 antibody CX-072." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3602. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3602.
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3602 Background: PROBODY therapeutics (Pb-Tx) are antibody prodrugs designed to reduce off-tumor, on-target toxicities. The mask inhibits Pb-Tx binding in the periphery yet can be removed by tumor-associated proteases, restricting target engagement to the tumor. This is the first report of preliminary clinical pharmacokinetic (PK) analysis supporting selection of the phase II dose for CX-072, an anti–PD-L1 Pb-Tx, from the ongoing phase I/II PROCLAIM-CX-072 study (NCT03013491). Methods: A quantitative systems pharmacology (QSP) model1 was used to project the CX-072 plasma trough level (Cmin) corresponding to 95% intratumoral receptor occupancy (RO). Human PK and anti-drug antibody (ADA) data were obtained at selected times postdose following IV administration of 0.03–30 mpk CX-072 in PROCLAIM-CX-072. Population PK (POPPK) modeling was performed with NONMEM v7.3.0. Exploratory analysis and simulations were done with R v3.3.1 or later. Covariates were selected for POPPK using forward addition ( P<0.05) followed by backward deletion ( P<0.01). Results: The preliminary POPPK analyses were informed using available PK data as of August, 2019 from 135 subjects receiving CX-072 Q2W as monotherapy in the dose-escalation and expansion cohorts of PROCLAIM-CX-072. A mixture model was used to capture time- and dose-dependent apparent ADA effect on clearance (CL). The preliminary POPPK model estimates for CX-072 CL and volume of distribution (Vd) were 0.306 L/day and 4.84 L, respectively. Statistically significant covariate effects included body weight on the central Vd and CL, and albumin on CL. The QSP model predicted a CX-072 Cmin of 13–99 nM would be required for 95% intratumoral RO. POPPK simulations suggested that >95% of patients receiving CX-072 10 mg/kg Q2W would meet or exceed this targeted Cmin regardless of ADA. Additional observed data indicated that the majority of patients receiving 10 mpk CX-072 Q3W × 4 with 3 mpk ipilimumab (IPI) Q3W × 4 in the CX-072-IPI combination part of PROCLAIM-CX-072 maintained the targeted Cmin. Simulations did not suggest there would be a clinically meaningful change in exposure following a fixed dose of CX-072 800 mg relative to the 10 mpk weight-based dose. Conclusions: Preliminary PK analysis supports selection of 800 mg CX-072 Q2W as the recommended monotherapy dose and 800 mg Q3W when combined with IPI. The combination of 800 mg CX-072 + 3 mpk IPI Q3W × 4 doses, followed by monotherapy administration of 800 mg CX-072 Q2W is being further explored in phase II. Reference: 1) Stroh M et al. CPT. 2019(9):676-84. Clinical trial information: NCT03013491 .
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Yee, Ka Lai, Huub Jan Kleijn, Thomas Kerbusch, Randolph P. Matthews, Mary Beth Dorr, Kevin W. Garey, and Rebecca E. Wrishko. "Population Pharmacokinetics and Pharmacodynamics of Bezlotoxumab in Adults with Primary and Recurrent Clostridium difficile Infection." Antimicrobial Agents and Chemotherapy 63, no. 2 (November 19, 2018): e01971-18. http://dx.doi.org/10.1128/aac.01971-18.
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ABSTRACT The fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of Clostridioides difficile (formerly Clostridium difficile) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-mg/kg of body weight bezlotoxumab were demonstrated in two phase 3 trials: the MODIFY I (ClinicalTrials.gov registration number NCT01241552) and MODIFY II (ClinicalTrials.gov registration number NCT01513239) trials. Here, a population pharmacokinetic (popPK) analysis, performed using data from the MODIFY I and II trials (n = 1,515) and from three phase 1 trials (n = 72) to characterize bezlotoxumab pharmacokinetics (PK) in phase 3 clinical trial participants and in healthy subjects, is reported. A stepwise covariate search was conducted to identify factors influencing PK. Post hoc-estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence. Bezlotoxumab PK were described by a two-compartment model with linear elimination and allometric scaling for clearance and the volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black versus nonblack), and albumin level as significant covariates, the impact of these factors was not clinically meaningful, based on the totality of the PK and clinical experience. Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10-mg/kg dose across the phase 3 trial population with no dose adjustments necessary over a broad demographic background.
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Schmidt, Keith T., Alwin D. R. Huitema, Thomas P. C. Dorlo, Cody J. Peer, Lisa M. Cordes, Linda Sciuto, Susan Wroblewski, et al. "Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors." Cancer Chemotherapy and Pharmacology 86, no. 4 (September 8, 2020): 475–86. http://dx.doi.org/10.1007/s00280-020-04134-9.
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Abstract Purpose NLG207 (formerly CRLX101) is a nanoparticle–drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. Methods From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. Results The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). Conclusion The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.
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van der Veen, A., RJ Keizer, W. de Boode, A. Somers, R. Brüggemann, R. ter Heine, and P. De Cock. "P99 Clinical validation of published vancomycin population PK models in critically ill neonates." Archives of Disease in Childhood 104, no. 6 (May 17, 2019): e58.2-e59. http://dx.doi.org/10.1136/archdischild-2019-esdppp.137.
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BackgroundVancomycin is commonly used for treatment of severe Gram+ neonatal infections. Currently, even with the use of optimized dosing regimens and therapeutic drug monitoring (TDM), target attainment rates are abominable, leaving patients at risk for therapeutic failure and toxicity. Model-informed precision dosing (MIPD) offers a large potential to improve therapy in the individual patient.The aim of this study was to identify a suitable model for bedside MIPD by assessing the predictive performance of published population pharmacokinetic (popPK) models.MethodsA literature search was conducted to identify parametric popPK models. PK vancomycin data were retrospectively collected from NICU patients at the Radboud University Hospital, Nijmegen, The Netherlands. The model predictive performance was assessed by comparison of predictions to observations, calculation of bias (Mean Percentage Errors, MPE) and imprecision (Normalized Root Mean Squared Errors, NRMSE). Evaluations included both a priori (model covariate input) and a posteriori (model covariate and TDM concentration input) scenarios.Results265 TDM measurements from 65 neonates (median postmenstrual age:32 weeks [range:25–45 weeks]; median weight:1281g [range:597–5360g]; median serum creatinine:0,48 mg/dL [range:0,15–1,28 mg/dL]) were used for model evaluation. Six popPK models were evaluated1–6. A posteriori predictions of all models were consistently more accurate and precise compared to the a priori (starting dose) predictions. PopPK models of Frymoyer et al. and Capparelli et al. consistently performed best through all evaluations in both the a priori and a posteriori scenario (MPE ranging from -18 to 6,4% in a priori scenario and -6,5 to -3,8% in a posteriori scenario; NRMSE ranging from 34 to 40% in a priori scenario and 23 to 24% in a posteriori scenario).ConclusionLarge differences in predictive performance of popPK models were observed. Repeated therapeutic drug monitoring remains necessary to increase target attainment rate. Best performing models for bedside MIPD were identified in our patient population.ReferencesZhao W, Lopez E, Biran V, et al. ( 2013). Vancomycin continuous infusion in neonates: Dosing optimisation and therapeutic drug monitoring. Arch Dis Child;98(6):449–453.Capparelli EV, Lane JR, Romanowski GL, et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. J Clin Pharmacol, 41:927–934.De Cock RFW, Allegaert K, Brussee JM, et al. ( 2014). Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res;31(10):2642–2654.Frymoyer A, Hersh AL, El-Komy MH, et al. ( 2014). Association between vancomycin trough concentration and area under the concentration-time curve in neonates. Antimicrob Agents Chemother, 58(11):6454–6461.Anderson BJ, Allegaert K, Van Den Anker JN, Cossey V, Holford NHG. ( 2006). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. Br J Clin Pharmacol;63(1):75–84.Germovsek E, Osborne L, Gunaratnam F, Lounis SA, Busquets FB, Sinha AK. ( 2019). Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data. J Antimicrob Chemother, 1–9.Disclosure(s)R. Keizer is an employee and stockholder of InsightRX.
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Hsu, Joy C., Felix Jaminion, Elena Guerini, Tomohiro Tanaka, Sophie Golding, Bogdana Balas, Ali Hassan Zeaiter, Peter N. Morcos, and Nicolas Frey. "Population pharmacokinetics (popPK) and exposure-response (ER) analyses bridge J-ALEX to the global population with an alectinib (ALC) 600mg bid dosing regimen." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20616-e20616. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20616.
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e20616 Background: J-ALEX showed superiority of ALC 300mg BID vs crizotinib (CRIZ) in Japanese ALK inhibitor naïve ALK-positive NSCLC patients (pts). PopPK and ER analyses were used to bridge J-ALEX data to the global population to confirm the appropriateness of ALC 600mg BID dose, used in global trials. Methods: The previous popPK analysis (Hsu et al, ASCO 2016) was updated to include PK data from J-ALEX and the ongoing global ALEX study to confirm any significant covariates influencing PK of ALC and major metabolite, M4, using Bayesian feedback analysis. ER analyses from J-ALEX (n=96) investigated the relationship between ALC and progression-free survival (PFS) by a Cox proportional hazards (CPH) analysis and key safety events using logistic regression. Results: The popPK models previously developed for pts who have progressed on, or are intolerant to CRIZ were able to adequately predict ALC and M4 PK in J-ALEX and ALEX. Body weight remained the only significant covariate influencing ALC and M4 PK. Administration of ALC 600mg BID in the global population ensures that ALC and M4 exposures across the body weight range are not inferior to those seen in Japanese pts receiving ALC 300mg BID, while lower doses would result in lower exposures. CPH analysis demonstrated a statistically significant relationship between ALC exposure and PFS in J-ALEX such that one third of pts in J-ALEX may benefit from a higher exposure of ALC (Table). ALC 600mg BID ensures the distribution of achieved exposures maximize the expected PFS benefit while lower ALC exposures could result in reduced efficacy. No significant exposure-safety relationships were identified in J-ALEX consistent with previous analyses conducted following ALC 600mg BID. Conclusions: ALC 600mg BID is the appropriate dose in the global ALK inhibitor naïve population. Clinical trial information: JapicCTI-132316. [Table: see text]
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Monk, Bradley J., Ignacio Romero, Whitney Graybill, Cristina Churruca, David M. O'Malley, Bente Lund, Oi Wah S. Yap, et al. "Niraparib exposure-response relationship in patients (pts) with newly diagnosed advanced ovarian cancer (AOC)." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 6051. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6051.
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6051 Background: Niraparib improves progression-free survival (PFS) in pts with newly diagnosed AOC after complete or partial response to first-line, platinum-based chemotherapy. In the PRIMA/ENGOT-OV26/GOG-3012 (PRIMA) trial, pts were treated with a fixed starting dose (FSD) of 300 mg QD until a protocol amendment introduced the individualized starting dose (ISD) regimen: 200 mg QD for pts with baseline bodyweight (BW) < 77 kg and/or platelet count (PC) < 150,000/µL, or 300 mg QD for pts with baseline BW ≥77 kg and PC ≥150,000/µL. Here, we developed a population pharmacokinetic (PopPK) model for niraparib and evaluated exposure-response relationships for pts receiving niraparib using safety and efficacy data from PRIMA. Methods: The PopPK model for niraparib was developed based on 7418 plasma samples from 1442 pts from 4 studies: PN001, NOVA, QUADRA, and PRIMA. PRIMA PK samples were collected on cycle 1, day 1 (C1D1), C2D1 pre-dose and 2 h post-dose, C4D1, and C8D1 pre-dose (or EOT if patient discontinued before C8D1). The relationship between PopPK model-based prospective exposure (average concentration [ Cave] until progression/death) and efficacy (PFS) were evaluated in pts receiving niraparib in both the homologous-recombination deficient (HRd) and overall population. The relationship between model-predicted exposure metrics and incidence of clinically relevant adverse events (AEs) was analyzed using univariate logistic regression in pts receiving niraparib. Results: Of 484 pts receiving niraparib in PRIMA, 480 had PK data and were included in the efficacy and safety analysis. The safety exposure-response showed significant associations ( p≤0.0128) between increasing niraparib exposure and increasing probability of experiencing any-grade and grade ≥3 AEs, except grade ≥3 hypertension. The incidence of AEs, including thrombocytopenia, was lower in pts who received a 200-mg ISD. Efficacy was not compromised in these pts. Conclusions: Niraparib exposure was associated with increased risk of select AEs. However, the ISD regimen decreased AE risk without compromising efficacy. Clinical trial information: NCT02655016.
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Kantasiripitak, W., K. van Hoeve, J. Sabino, S. Vermeire, I. Hoffman, P. Declerck, D. Thomas, M. Ferrante, and E. Dreesen. "P304 Rational infliximab induction dosing to achieve long-term deep remission in children with Inflammatory Bowel Diseases." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S332—S333. http://dx.doi.org/10.1093/ecco-jcc/jjab076.428.
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Abstract Background Adequate infliximab (IFX) trough concentrations (TCs) during induction treatment are predictive for long-term clinical and endoscopic remission in paediatric patients with inflammatory bowel diseases (IBD). However, under the approved weight-based dosing (5 mg/kg), children often have low IFX TCs, since the relationship between bodyweight and the IFX pharmacokinetic (PK) parameters is nonlinear. Therefore, there is a need to optimise paediatric dosing to engage optimal IFX TCs during induction treatment. Methods Fifty-two paediatric patients with IBD (34 Crohn’s disease (CD), 18 ulcerative colitis (UC)) contributed IFX samples (246 intermediate and 150 trough samples) during either induction treatment (n=32) or maintenance treatment (n=20). A population PK (popPK) model was developed to describe the relationship between IFX dose and exposure. The previously published IFX popPK model based on data of 112 children with CD in the Phase 3 REACH trial was used as a frequentist prior to inform parameter estimation using NONMEM. Our popPK model was used to simulate IFX TCs during induction treatment under different induction dosing regimens (5 mg/kg, 7.5 mg/kg, and 10 mg/kg IFX at weeks 0, 2, and 6). Probabilities of TC target attainment (PTA) were compared. The TC target, associated with a 75% probability of achieving deep remission (DR) at six months after initiating IFX treatment, was identified using a logistic regression model and a ROC analysis. DR was defined as combined endoscopic remission (Simple Endoscopic Score for CD <3 or Mayo endoscopic sub-score 0) and corticosteroid-free clinical remission (Paediatric CD or UC Activity Index <10). Results The median boyweight was 44 kg (range 15-92 kg). A 2-compartment popPK model with first-order elimination described IFX concentrations well (Table 1). The IFX clearance by weight increased with decreasing bodyweight, decreasing serum albumin and absence of immunomodulator combo-therapy. Also, the IFX volume of distribution in the central and peripheral compartment by weight increased with decreasing bodyweight. A total of 18/32 (56%) patients in the induction treatment achieved DR at six months. An IFX TC of 23.0 mg/L at week 6 was identified as the TC target (100% sen, 33% spe, 100% npv, and 50% ppv). Children with a bodyweight less than 30 kg could only reach a 50% PTA when receiving 10 mg/kg IFX combo-therapy during induction (Figure 1). While children with a bodyweight above 30 kg had more than 50% PTA when receiving either 10 mg/kg IFX monotherapy or 7.5 mg/kg IFX combo-therapy (Table 2). Conclusion IFX doses higher than 5 mg/kg are needed during induction in children with IBD to facilitate the attainment of the TC target, thereby increasing the chance of long-term DR.
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Tapia Artiles, Carlos, J. Samuel Pérez-Blanco, Dolores Santos Buelga, and María José García Sánchez. "Farmacocinética poblacional de fenitoína en pacientes adultos." FarmaJournal 5, no. 2 (November 9, 2020): 15–26. http://dx.doi.org/10.14201/fj2020521526.
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La fenitoína (DPH) es un antiepiléptico considerado de primera elección en el tratamiento de las crisis focales y convulsiones tónico-clónicas. DPH presenta elevada unión a proteínas plasmáticas, un comportamiento cinético no lineal dependiente de la dosis, elevada variabilidad cinética interindividual y un estrecho margen terapéutico; estas características aconsejan su monitorización para optimizar su balance eficacia/toxicidad. El objetivo de este trabajo fue la caracterización de la farmacocinética de DPH en población adulta.
Concentraciones en estado de equilibrio de DPH procedentes de 215 pacientes adultos fueron utilizadas para desarrollar un modelo farmacocinético poblacional (PopPK) aplicando una metodología de efectos mixtos no lineales con el programa NONMEM v.7.3.
La cinética de DPH fue descrita adecuadamente mediante un modelo monocompartimental con absorción de orden cero y cinética de eliminación no lineal ajustada a la ecuación de Michaelis-Menten. Edad, peso, magnitud de dosis y comedicación con ácido valproico han mostrado influencia sobre la velocidad de eliminación de DPH, reduciendo su variabilidad de forma considerable.
Se ha obtenido un modelo PopPK preliminar que ha mostrado una adecuada capacidad descriptiva y predictiva en población adulta en un amplio rango de dosis (50-800 mg/día). No obstante, se precisa su aplicación en el contexto clínico para confirmar su validez.
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Toja-Camba, Francisco José, Nerea Gesto-Antelo, Olalla Maroñas, Eduardo Echarri Arrieta, Irene Zarra-Ferro, Miguel González-Barcia, Enrique Bandín-Vilar, et al. "Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics." Pharmaceutics 13, no. 7 (June 23, 2021): 935. http://dx.doi.org/10.3390/pharmaceutics13070935.
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Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.
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Shi, Yuankai, Yongping Song, Yan Qin, Qingyuan Zhang, Xiaohong Han, Xiaonan Hong, Dong Wang, et al. "First China Approved Rituximab Biosimilar HLX01: Pharmacokinetics, Safety and Efficacy Comparison to Reference Rituximab in the Phase 3 Diffuse Large B-Cell Lymphoma Study." Blood 134, Supplement_1 (November 13, 2019): 2878. http://dx.doi.org/10.1182/blood-2019-130603.
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Background In February 2019, the National Medicinal Products Administration (NMPA) approved the first China-manufactured rituximab (RTX) biosimilar, HLX01, for the treatment of non-Hodgkin's lymphoma in accordance to the development of biosimilar guidelines with stepwise approach demonstrating bioequivalence. HLX01 was also developed as a novel drug for rheumatoid arthritis (RA) since the indication has not been approved in China. Studying pharmacokinetics (PK) in healthy volunteers as the most sensitive population is not ethically acceptable due to the safety concerns associated with rituximab. The NMPA approval was based on a comprehensive data package of extensive analytical characterization, non-clinical studies, clinical trials and the population PK (PopPK) model. Here, we report the Phase 3 confirmatory study aimed to establish equivalence in safety and efficacy of HLX01 and RTX in patients with diffuse large B-cell lymphoma (DLBCL) and the PopPK model derived from the PK data of HLX01 and RTX in RA compared the PK data in DLBCL and the Caucasian RTX data in RA. Methods In this multicenter, randomized, double-blind, parallel active-controlled, Phase 3 study (NCT02787239), treatment-naïve adults aged 18-80 years with histologically confirmed CD20+ DLBCL were treated with cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) and randomly assigned at 1:1 ratio to co-administer with HLX01 (H-CHOP) or RTX (R-CHOP) every 21 days cycle treatment. The primary efficacy endpoint was the best overall response rate (ORR) for HLX01 and RTX over 6-cycle therapy. The therapeutic equivalence was concluded if 95% confidence interval (CI) of the difference in best ORRs between the two treatments fell within the pre-specified range of ±12%. Additional endpoints included long-term efficacy outcomes, safety and immunogenicity profiles and sparse PK samplings for peak and trough levels comparison. The PopPK model was developed from the randomized, double-blind PK study (NCT03355872) of HLX01 and RTX in 196 patients with moderately to severely active RA (serum sample=4289) using non-linear mixed-effect modeling (NONMEM®) and the first-order estimation with interaction (FOCEI) method. The PK and PK-pharmacodynamic relationship being characterized with various covariates were tested on forward addition (p<0·01) / backward elimination (p<0·001). After the final model being examined with Bayesian bootstrapping, visual predictive check (VPC) and 1000 simulations from the observed covariates, external validations were tested using the Phase 3 PK data in 110 patients with DLBCL and comparing the Chinese data with other races by simulations from several published PK data in Caucasian RA patients. Results The best ORRs [95% CI] within 6 cycles therapy were 94·1% [89·77%, 97·04%] in H-CHOP and 92·8% [88·19%, 96·00%] in R-CHOP with the ORR difference (1·4% [−3·59%, 6·32%], p=0·608) fell in the pre-specified equivalent margin. Long-term efficacy and safety profiles, including the incidence of treatment-emergent adverse events (p=1·000) and serious adverse events (p=0·752), were similar in two treatment groups (Table 1). The best model fit for the PopPK was a two-compartment model with first-order elimination. The estimated clearance (CL), central volume (Vc), peripheral-compartment volume and clearance-of-distribution from the central-to-peripheral-compartment were 27·32%, 16·56%, 21·61%, and 40·79%, respectively. The correlation between CL and Vc was 0.02239. The observed concentrations and simulations for the corresponding model predicted all subjects in the dataset with no significant difference in area under the curve from zero to infinity between two clinical studies of HLX01 and RTX. The PK results were also similar to the existing model in Caucasian. Conclusion HLX01 demonstrated equivalent safety and efficacy to the reference RTX with no clinically meaningful differences in CD20+ DLBCL. The PopPK model successfully proved the PK similarity between HLX01 and RTX in patients with RA or DLBCL with no racial differences. Based on the totality of evidence with the results from this Phase 3 study and PopPK modeling, China NMPA approved HLX01 as the first China RTX biosimilar with the potential to provide alternative treatment option for patients. To the best of our knowledge, we are the first reporting the establishment of biosimilarity with RTX in DLBCL patient population. Disclosures Zhao: Certara Strategic Consulting China: Employment. Hong:Shanghai Henlius Biotech, Inc.: Employment. Ma:Shanghai Henlius Biotech, Inc.: Employment. Cheng:Shanghai Henlius Biotech, Inc.: Employment. Ting:Shanghai Henlius Biotech, Inc.: Employment. Li:Shanghai Henlius Biotech, Inc.: Employment. Jiang:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Liu:Shanghai Henlius Biotech, Inc.: Employment. Zhang:Shanghai Henlius Biotech, Inc.: Employment. Chai:Shanghai Henlius Biotech, Inc.: Employment. Yao:Shanghai Henlius Biotech, Inc.: Employment. Luk:Shanghai Henlius Biotech, Inc.: Employment.
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Pierre, Vadryn, Bruno Francois, Martha Hernandez-Illas, Miguel Sánchez Garcia, Yuling Wu, Philippe Eggimann, Pierre-Francois Laterre, et al. "1557. Population Pharmacokinetics of Suvratoxumab (MEDI4893), an Extended Half-life Staphylococcus aureus Alpha Toxin-Neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S568—S569. http://dx.doi.org/10.1093/ofid/ofz360.1421.
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Abstract Background Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 μg/mL at 30 days post-dose. Methods The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days. Results A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability (<45% CV) was estimated for key PK parameters. An estimated two-fold increase in MV patients’ volume of distribution parameters compared with healthy volunteers explained the observed Cmax differences between the two groups (1145±369 μg/mL vs. 1783±396 μg/mL) (Figures 2 and 3). Although age, MV status and days on MV post-dose appeared to be associated with higher systemic clearance (CL) in the model, this estimate could be biased due to limited PK data available for only one half-life (~90 days) of the drug in MV patients (Figure 2). More patients achieved suvra levels above the PK target following the 5 g (73.5%; 50/68) vs. 2 g dose (7.6%; 1/13) at 30 days post-dose. Conclusion MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients. Disclosures All authors: No reported disclosures.
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de Castro-Suárez, Niurys, Mirjam N. Trame, Mayra Ramos-Suzarte, José M. Dávalos, Raymed A. Bacallao-Mendez, Anaelys R. Maceo-Sinabele, Víctor Mangas-Sanjuán, Gledys Reynaldo-Fernández, and Leyanis Rodríguez-Vera. "Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease." Pharmaceutics 12, no. 12 (November 26, 2020): 1147. http://dx.doi.org/10.3390/pharmaceutics12121147.
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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.
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Hall, Ronald G., Jotam Pasipanodya, William C. Putnam, John Griswold, Sharmila Dissanaike, Raja Reddy Kallem, Vindhya Edpuganti, and Indhumathy Subramaniyan. "1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S670—S671. http://dx.doi.org/10.1093/ofid/ofaa439.1501.
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Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)
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Savelieva, Marina, Margaret M. Woo, Harald A. Weber, Samit Hirawat, Sofia Paul, Joanne Schindler, and Roland Fisch. "Population Pharmacokinetics of Panobinostat (LBH589) in Patients with Advanced Solid Tumors and Hematologic Malignancies Following Intravenous and Oral Administration." Blood 114, no. 22 (November 20, 2009): 3780. http://dx.doi.org/10.1182/blood.v114.22.3780.3780.
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Abstract Abstract 3780 Poster Board III-716 Introduction Panobinostat (LBH589), a hydroxamic acid derivative, is one of the most potent deacetylase inhibitors (DACi), with anti-tumor activity in a wide variety of preclinical xenograft models, and has shown promising clinical activity in patients with Hodgkin lymphoma and multiple myeloma. A population pharmacokinetic (PopPK) analysis was performed to characterize the extent and variability of panobinostat exposure in patients with advanced cancer and to evaluate the influence of selected covariates on exposure. Patients and methods Panobinostat concentrations in plasma were evaluated in 500 patients enrolled in five Phase I studies and four Phase II studies as asingle-agent administration. Patients received oral panobinostat at doses of 10–80 mg on Days 1, 3, and 5, weekly [QW], or every other week [QOW], or on Days 1 and 4 QW in three Phase I oral studies. Intravenous (i.v.) panobinostat was delivered at doses from 1.2 to 20 mg/m2 in 4 schedules (Days 1–7; or Days 1–3 QW or QOW; or once weekly for 3 weeks) in two Phase I i.v. studies. Panobinostat was also orally administered at 20 mg, on Days 1, 3 and 5 QW, in patients with cutaneous T-cell lymphoma, chronic myelogenous leukemia, and multiple myeloma in four Phase II oral studies. Panobinostat PopPK was characterized by a compartmental non-linear mixed-effects model. Results Panobinostat concentration–time data were well described by a linear 3-compartment model with first-order absorption. The model estimated the population median (CV%) of the total clearance (CL) to be 28.6 L/h (78%) and the volume of distribution (V) 27.2 L (54.8%). Absolute oral bioavailability is 30%. The relative bioavailabilities of oral formulations 1 (Phase II formulation) and 2 (Phase I formulation) are 17% and 23%, respectively. The analysis showed no effect on panobinostat clearance by gender, race, co-medications, disease state, or renal function as measured by plasma creatinine clearance. Body surface area (BSA 1.4–3.4 m2) and age (16–88 years) in the ranges studied were non-linear covariates for panobinostat clearance and volume. Conclusions The pharmacokinetics of panobinostat are linear and time independent. BSA may have clinical utility in predicting panobinostat clearance. The PopPK model generated from this study allows for future pharmacokinetic–pharmacodynamic correlation and application in optimizing the use of panobinostat. Disclosures: Savelieva Praz: Novartis: Employment. Woo:Novartis: Employment. Weber:Novartis Pharma AG: Employment. Hirawat:Novartis: Employment. Paul:Novartis: Employment. Schindler:Novartis: Employment. Fisch:Novartis : Employment.
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Alifrangis, Lene, Rik Schoemacker, Niels Jorgen Ostergaard Skartved, Rikke Hald, Maria Düring, Clara Montagut, Guillem Argiles, et al. "Population pharmacokinetics (popPK) of Sym004 to evaluate the effect of intrinsic and extrinsic factors on exposure in metastatic colorectal cancer (mCRC)." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 496. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.496.
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496 Background: Sym004 consists of two anti-EGFR monoclonal antibodies (futuximab and modotuximab) directed against non-overlapping epitopes in the EGFR domain III. Sym004 induces rapid and efficient removal of the EGFR from the cancer cell surface by triggering EGFR internalization and degradation and has shown promising efficacy in mCRC patients. Based upon a post-hoc analysis of a Phase 2 study, a Phase 3 trial in genomically selected mCRC patients is in preparation. Methods: The aim was to establish a popPK model for Sym004 in order to i) evaluate impact of covariates (intrinsic and extrinsic factors) on Sym004 exposure and ii) provide exposure metrics for a PK/PD analysis. Sym004 serum concentrations were obtained from 330 patients with mCRC (n = 247) or advanced solid tumors (studies Sym004-01, Sym004-02, Sym004-05 and Sym004-06). Sym004 (0.4-18 mg/kg) was dosed by i.v. infusion weekly or every 2nd week, or as a 9 mg/kg loading dose followed by 6 mg/kg weekly (9/6 mg/kg weekly). Non-linear mixed effects modelling was done in NONMEM v7.3.0. Covariates evaluated included body weight, age, sex, race, albumin, renal function, hepatic function, tumor type and size, ECOG and previous anti-EGFR treatments. Results: The base popPK model was a 2-compartment model with linear and non-linear Michaelis-Menten-type elimination and a priori inclusion of body weight on CL, Vmax, V1 and V2. The model captured the non-linear PK well. The final covariate model retained covariates whose point estimates were outside the range of 0.8 to 1.25 and whose 90% confidence intervals did not overlap with the null value and included only body weight and albumin. Inter-individual variability was estimated for CL, Vmax and V1 and was in the range of 18-30%. Simulations were used to assess the clinical relevance of the covariates as judged by the magnitude of the change in exposure of the Phase 3 dose regimen of 9/6 mg/kg weekly. Conclusions: The popPK model described the Sym004 PK data well. No covariates were present that changed the Sym004 exposure in a clinically significant manner which would necessitate a dose modification. The model is suitable for simulating the Sym004 PK for PK/PD analyses. Clinical trial information: NCT01117428,NCT01417936,NCT02083653,NCT01955473.
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Winchell, Gregory A., Rik de Greef, Rebecca E. Wrishko, Eric Mangin, Hetty Waskin, and Christopher Bruno. "1558. A Population Pharmacokinetic Model for Posaconazole Intravenous Solution and Oral Powder for Suspension Formulations in Pediatric Patients With Neutropenia." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S569. http://dx.doi.org/10.1093/ofid/ofz360.1422.
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Abstract Background Posaconazole is approved in adults for prophylaxis and treatment of invasive fungal disease. Two formulations that offer weight-based dosing—intravenous (IV) and oral powder for suspension (PFS)—are being evaluated in children. A population pharmacokinetic (popPK) approach was used to characterize and predict the PK exposure of posaconazole PFS and IV formulations in children to identify dosages associated with achieving a target PK of 1200 ng/mL as the mean Cavg and individual Cavg ≥500 ng/mL and <2500 ng/mL in ~90% of patients. Methods A popPK model was developed through nonlinear mixed-effects modeling using data obtained from a trial in children with neutropenia (ClinicalTrials.gov, NCT02452034; Merck protocol, MK-5592-097). Three dose cohorts (3.5, 4.5, and 6 mg/kg/day [≤300 mg/day]) were studied in two age groups (2–<7 years and 7–17 years). Posaconazole IV was administered twice on day 1 then once daily through at least day 10, followed by PFS once daily through day 28 at clinician discretion. A compartmental model, including both formulations, was fit to the data. Model selection was based on the Log-Likelihood Criterion, goodness-of-fit plots, and scientific plausibility. Significance of the covariates was assessed in a stepwise forward inclusion/backward procedure. An additional assessment characterized the impact of different food covariates on bioavailability. Results An open one-compartmental PK model with first-order absorption and estimated bioavailability, as well as allometrically scaled effects of body weight on clearance and volume, adequately described the PK of posaconazole IV and PFS formulations. Model predictions are shown in the Table. Effects of the different food covariates were not statistically significant. Simulations indicated that for the 6-mg/kg/d dose, model-predicted Cavg generally met PK targets. Model-predicted Cavg was ≥500 ng/mL in >90% of subjects in all cohorts. The 1200-ng/mL target geometric mean Cavg was achieved for all but the 2–<7 years cohort receiving the PFS formulation. Conclusion This popPK-based analysis demonstrated that the 6-mg/kg/d dose of IV or PFS posaconazole formulation (≤300 mg/days) is appropriate for children (2–17 years) and that PFS can be administered without regard to food. Disclosures All authors: No reported disclosures.
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Gao, Ling, Yiu-Keung Lau, Ran Wei, Lisa O’Brien, Amanda Long, Yongzhe Piao, and Paolo Abada. "Evaluating clinical impact of a shortened infusion duration for ramucirumab: a model-based approach." Cancer Chemotherapy and Pharmacology 87, no. 5 (February 2, 2021): 635–45. http://dx.doi.org/10.1007/s00280-020-04223-9.
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Abstract Purpose We investigated the impact of infusion duration (30 and 60 min) on the pharmacokinetic profile of ramucirumab using a population pharmacokinetic (PopPK) modeling approach. We also assessed the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration) using ramucirumab phase II/III study data. Methods The impact of different infusion durations (30 vs. 60 min) on the time-course of ramucirumab concentration profiles were evaluated using a PopPK model, established using ramucirumab pharmacokinetic data from 2522 patients. Logistic regression was used to evaluate the association between ramucirumab infusion rate and incidence of immediate IRRs in clinical trials. Results Ramucirumab time-course concentration profiles were equivalent following a 30- or 60-min infusion. In the pooled clinical study dataset, 254 of 3216 (7.9%) patients receiving ramucirumab experienced at least one immediate IRR (any grade). When grouped according to infusion rate quartile, the incidence of immediate IRRs (any grade or grade ≥ 3) was similar across quartiles; findings were confirmed in sensitivity analyses. The risk of immediate IRRs was not found to be associated with infusion rate based on multivariate logistic analysis. Conclusion Shortening the infusion duration of ramucirumab from 60 to 30 min has no impact on ramucirumab exposure. Analysis of trial data found no relationship between an increased risk of immediate IRRs and a faster infusion rate. Such a change in infusion duration is unlikely to affect the clinical efficacy or overall safety profile of ramucirumab.
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Katsube, Takayuki, Nao Kawaguchi, Roger Echols, Toshihiro Wajima, and David P. Nicolau. "1302. Cefiderocol Population Pharmacokinetics and Probability of Target Attainment in Plasma and Epithelial Lining Fluid in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infections." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S665. http://dx.doi.org/10.1093/ofid/ofaa439.1485.
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Abstract Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. The aim of this study was to perform population pharmacokinetic (PopPK) analysis and evaluate probability of target attainment (PTA) in plasma and epithelial lining fluid (ELF) based on a modeling and simulation approach. Methods PopPK analysis in plasma was conducted using 3427 concentration data from 425 patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), complicated urinary tract infection (cUTI), or acute uncomplicated pyelonephritis in 3 Phase 2 or 3 studies (NCT03032380, NCT02714595, and NCT02321800), and 91 subjects without any infection in Phase 1 studies. In addition, intrapulmonary modeling was conducted using ELF concentration data from 7 pneumonia patients (NCT03862040) and 20 healthy subjects. Monte-Carlo simulations were performed by generating 1000 virtual patients for each infection site (pneumonia, BSI/sepsis, or cUTI) to predict PTA for 75% of time for which free drug concentration in plasma or ELF (only pneumonia patients) exceeds the minimum inhibitory concentration (MIC; 0.25–16 µg/mL) over dosing interval following CFDC 2 g q8h infused over 3 hours with dose adjustment based on renal function, including augmented renal clearance. Results The developed PopPK model described the plasma and ELF CFDC concentrations. Creatinine clearance, body weight, infection site, and albumin concentration were statistically significant covariates on CFDC PK in plasma. There were no clinically significant differences in CFDC plasma exposure based on infection site or with/without ventilation. The penetration ratio of ELF to free plasma in pneumonia patients (0.340) was 1.3-fold higher than that in healthy subjects (0.263). As shown in the table below, plasma PTA was >90% against MICs ≤4 μg/mL, regardless of infection site and renal function. ELF PTA in pneumonia patients was >90% against MICs ≤2 μg/mL and >85% against MICs ≤4 μg/mL, regardless of renal function. Table. Probability of Target Attainment for 75% fT>MIC or 75% fT>MIC,ELF Conclusion The recommended dosing regimen (2 g, q8h, 3-hr infusion) adjusted by renal function provided adequate exposure to CFDC in patients with infections caused by Gram-negative pathogens, irrespective of infection site and renal function. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)
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Kantasiripitak, W., B. Verstockt, T. Lobatón, D. Thomas, A. Gils, S. Vermeire, M. Ferrante, and E. Dreesen. "P542 The effect of age on infliximab pharmacokinetics in patients with inflammatory bowel disease." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S462—S463. http://dx.doi.org/10.1093/ecco-jcc/jjz203.670.
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Abstract Background Data remain scarce in terms of efficacy and safety of infliximab (IFX) treatment in elderly patients with inflammatory bowel disease.1 Our aim was to employ a population pharmacokinetic (popPK) model to improve our understanding of factors impacting variability in IFX exposure in elderly patients with ulcerative colitis (UC) and Crohn’s disease (CD). Methods IFX concentration–time data during induction therapy (week 2, 6 and 14) of 104 patients were obtained from a retrospective case–control study2 (n = 79) and a single centre database search (n = 25) at our institution. Patients ≥65 years old were categorised as elderly. A popPK model was developed using NONMEM 7.4. Relationships between IFX exposure and the first endoscopic remission (ER) assessment after the start of IFX therapy (absence of ulceration [CD] and Mayo endoscopic sub-score ≤0 [UC]) were evaluated. Results Median age was 62 years (IQR 38–68). A total of 46 of 104 patients (44%) were elderly. A one-compartment model with linear clearance showed adequate descriptive and predictive ability. The estimated popPK parameters (typical value [%RSE]) were clearance CL (0.346 l/day [4%]) and volume of distribution V (6.42 l [5%]). The elimination half-life of IFX in the elderly was not significantly different from the non-elderly (12.6 days vs. 11.4 days, p = 0.356). IFX clearance was higher with the presence of antibodies to IFX (ATI; drug-tolerant assay; 32% higher), higher fat-free mass (FFM; 1.4% per kg), lower serum albumin (4.5% per g/l), and younger age (0.6% per year). These covariates explained 10% of interindividual variability (IIV) in IFX CL. However, 33% of the variability remained unexplained. Contrary to Paul et al.3, proportions of patients with ATI were not significantly different between elderly and non-elderly (13% [6/46] vs. 14% [8/58], p = 1.000). FFM and serum albumin were significantly lower in elderly patients (p = 0.007 and p = 0.0004, respectively). Due to the large remaining IIV, IFX exposures (trough concentrations and estimated area under the PK curve) were not significantly different between elderly and non-elderly (Figure 1). A total of 19/72 patients (26%, 32/104 had no endoscopy data) achieved ER. There was no significant difference between the proportion of elderly and non-elderly with ER (p = 1.000). IFX trough concentrations at w6 were significantly higher in patients achieving ER (p = 0.016). Conclusion Older age is an independent predictor of lower clearance. However, the effect of age did not pronounce on infliximab exposure in our elderly patient cohort as a result of confounding effects of fat-free mass and serum albumin. References
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Wang, Xiaofeng, Suresh Mallikaarjun, and Ekaterina Gibiansky. "Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis." Antimicrobial Agents and Chemotherapy 65, no. 1 (October 26, 2020): e01202-20. http://dx.doi.org/10.1128/aac.01202-20.
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ABSTRACTA population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200-mg and higher doses (250 and 300 mg) were 76% and 58% of a 100-mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was higher, and lag time was shorter, following a morning dose than an evening dose. Relative bioavailabilities in patients in Northeast Asian and Southeast Asian regions were 53% and 40% higher, respectively, than in patients in non-Asian regions. Apparent clearance was higher (to the power of −0.892) in patients with hypoalbuminemia (albumin levels of <3.4 g/dl). Coadministration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18 to 64 years), mild or moderate renal impairment, anti-TB antibiotic resistance status, HIV status, or markers of hepatic dysfunction or by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP3A4 inhibitors and inducers, or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating that the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.
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Vande Casteele, Niels, Filip Baert, Sumin Bian, Erwin Dreesen, Griet Compernolle, Gert Van Assche, Marc Ferrante, Severine Vermeire, and Ann Gils. "Subcutaneous Absorption Contributes to Observed Interindividual Variability in Adalimumab Serum Concentrations in Crohn’s Disease: A Prospective Multicentre Study." Journal of Crohn's and Colitis 13, no. 10 (March 1, 2019): 1248–56. http://dx.doi.org/10.1093/ecco-jcc/jjz050.
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Abstract Background and Aim Therapeutic drug monitoring is used to optimise adalimumab therapy in patients with Crohn’s disease [CD]. However, the interindividual variability in drug absorption and the quantitative effect on drug clearance of anti-adalimumab antibodies [AAA], measured with a drug-resistant assay, are unclear. We aimed to characterise adalimumab population pharmacokinetics [PopPK] and identify determinants of interindividual variability in patients with CD. Methods In a prospective multicentre open-label cohort study in 28 patients with CD starting adalimumab therapy peak, intermediate, and trough serum samples were analysed for adalimumab and AAA concentrations using a drug resistant assay. Adalimumab concentration-time data were analysed by non-linear mixed effects modelling and were adequately described by a PopPK model with first-order absorption and one-compartment disposition with linear elimination. Clinical remission at Week 12 [W12] was defined as a Harvey-Bradshaw index ≤4. Results The absorption rate, volume of distribution, and clearance estimates of a typical patient were respectively 0.343 /day, 7.8 L, and 0.330 L/day. A 4-fold difference in the range of adalimumab concentrations was observed 7 days after the first dose and found to be inversely correlated with baseline lean body weight [LBW], soluble tumour necrosis factor [s-TNF], and s-TNF receptor-1 whereas positive AAA and higher LBW were found to be important predictors of accelerated clearance. An adalimumab concentration at W12 of >7.3 µg/mL was significantly associated with achieving clinical remission at W12. Conclusion Variability in subcutaneous drug absorption is an important contributor to the observed interindividual variability in adalimumab concentrations, in addition to drug clearance [ClinicalTrials.gov NCT02450513].
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Dreesen, E., S. Berends, D. Laharie, G. D’Haens, S. Vermeire, A. Gils, and R. Mathôt. "DOP14 Modelling of the relationship between infliximab exposure, faecal calprotectin, and endoscopic remission in patients with Crohn’s disease." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S052—S053. http://dx.doi.org/10.1093/ecco-jcc/jjz203.053.
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Abstract Background Less than 50% of patients with Crohn’s disease (CD) starting infliximab (IFX) therapy achieve endoscopic remission (ER). Evidence for the benefits of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring remains scarce. We aimed to develop a population (pop)PK/PD model to characterise the IFX dose-exposure-biomarker-response (faecal calprotectin [fCal] and ER) relationship in patients with CD. Methods Analyses were performed using data of a phase 4 dose-escalation study (TAILORIX). Patients started standard 5 mg/kg IFX induction therapy at weeks [w]0, 2 and 6. From w14 through w54, the IFX dose could be irreversibly doubled based on one of the three monitoring algorithms.1 Endoscopies were performed at w0, 12 and 54. Three sequential models were developed: A 2-compartment popPK model linking IFX dose to exposure, an indirect response popPK-PD model describing the inhibitory effect of IFX exposure on fCal, and a first-order Markov popPD model linking fCal to transitions between states of ER (CD endoscopic index of severity <3), no ER and dropout (Figure 1). All modelling and simulation were performed using NONMEM 7.4. Results The study included 116/122 (95%) patients with CD enrolled in TAILORIX who had ≥1 detectable IFX serum concentration. In the developed models, it was shown that IFX clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of antibodies to IFX (transiently). Baseline fCal increased with increasing CRP and decreasing platelet count. Lower fCal increased probability of attaining ER and decreased probability of losing ER. Probability of dropping out given an earlier state of absence of ER increased with elapsing time. Simulations of 150 000 patients receiving 5, 7.5 or 10 mg/kg IFX (1:1:1) resulted in a flat dose–response curve due to large interindividual variability in PK and PD (Figure 2, top panels). The predicted fraction of patients achieving ER at w12 was 45.1% [30.3–60.5] (median [IQR]) when on 5 mg/kg IFX (~46.4% observed in data). However, simulations of 10 mg/kg IFX induction doses predicted only a slight increase in the fraction of patients achieving ER at w12 to 47.5% [32.0–62.6]. This minor benefit at the population level argues against systematic 10 mg/kg induction dosing in all patients. A similar observation was done during maintenance therapy, where 70.8% [62.6–75.5] of all simulated patients maintained ER at w54 (~72.2% observed in data) (Figure 2, right panels). Conclusion Model-informed infliximab dose optimisation towards a predefined fCal concentration—while accounting for PK and PD variability—may improve the effectiveness of infliximab therapy (eg. 64% chance of ER at w12 ~100 μg/g fCal at w6). Reference
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Djebli, Nassim, Felix Jaminion, Johann Laurent, Francois Mercier, Nicole A. Kratochwil, Ann-Marie E. Bröske, Natalie Dimier, et al. "Population Pharmacokinetics and Novel Exposure-Response Analyses to Inform Optimal Biologic Dose Selection for CD20-TCB, a T-Cell-Engaging Bispecific Antibody, in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma." Blood 134, Supplement_1 (November 13, 2019): 3799. http://dx.doi.org/10.1182/blood-2019-123712.
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Introduction: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. An ongoing Phase I dose-escalation study (NP30179; NCT03075696) has shown promising antitumor activity and acceptable safety in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts) (Dickinson et al. ICML 2019). We investigated population pharmacokinetics (popPK) and exposure-response (E-R) relationships for CD20-TCB in NP30179. Methods: Indolent (i) and aggressive (a) R/R NHL pts received CD20-TCB doses of 0.005 to 25mg every 2 or 3 weeks following single 1000mg obinutuzumab (G) pre-treatment (Gpt) on Cycle 1 Day −7 to mitigate for cytokine release syndrome (CRS). Serial and spare PK data collected from pts were used to develop a popPK model in NONMEM v7.4. Physiologically relevant covariates were investigated for their potential influence on CD20-TCB PK variability. Using the previously established G popPK model (Gibiansky et al. CPT Pharmacometrics Syst Pharmacol 2014;3:e144), full G concentration-time profiles were constructed in order to estimate CD20-TCB receptor occupancy (RO%) in the presence of G concentrations competing for CD20 receptors over time. E-R relationships between CD20-TCB time-averaged RO% (AvgRO%) up to Cycle 3 Day 1 and objective response rate (ORR) and complete response rate (CRR) were investigated in aNHL pts who reached Cycle 3 Day 1, and the relationship between CD20-TCB AvgRO% over the first 24 hours (as the majority of events occurred within the first 24 hours) and CRS, the most common safety event, as defined by Lee et al. (Blood 2014;124:188-95), was investigated in iNHL and aNHL pts combined using logistic regression. Results: The popPK analysis included 139 iNHL and aNHL pts with at least one PK sample. The E-R analysis for efficacy included 76 aNHL pts with PK and efficacy data at Cycle 3 Day 1. The E-R analysis for safety included 121 iNHL and aNHL pts with PK and safety data. CD20-TCB PK was best described using a two-compartment PK model with linear clearance. Body weight had a statistically significant influence on PK and was retained using theory-based allometric scaling. There were no obvious differences in PK between iNHL and aNHL pts. In aNHL pts, logistic regression analyses demonstrated a significant positive E-R relationship between AvgRO% up to Cycle 3 Day 1 and efficacy (ORR and CRR, p=0.007; Figure 1 for CRR). In the highest tertile of AvgRO% (≥0.48%), the observed ORR was 76% versus 38.5% (<0.041%) and 52% (0.041%-0.48%) in the lower tertiles; CRR was 48% versus 19.2% and 36%. A significant positive E-R relationship was identified between CD20-TCB AvgRO% over the first 24 hours and Grade (Gr) ≥2 CRS (p<0.001; Figure 2), consistent with the clinical safety profile showing first-dose-dependent CRS, with the majority of events occurring within the first 24 hours (Dickinson et al. ICML 2019). Following administration of a CD20-TCB dosing regimen of 10/16mg q3w (10mg in Cycle 1 followed by 16mg thereafter), the AvgRO% (median [P10-P90]) up to Cycle 3 was 0.466% (0.249%-1.63%), corresponding to an anticipated CRR at Cycle 3 of 43.6% (38.2%-54.7%) based on the exposure-efficacy model (Figure 1), in line with the clinical CRR seen in the 10 and 16mg q3w dose cohorts previously reported (Dickinson et al. ICML 2019). The resulting AvgRO% over the first 24 hours following an initial 10mg dose in Cycle 1 was 0.797% (0.344%-1.78%), corresponding to a Gr ≥2 CRS rate of 36.7% (27.1%-45.4%) based on the exposure-safety model (Figure 2), in line with the CRS incidences observed in the 10mg q3w dose cohort reported previously (Dickinson et al. ICML 2019). These PopPK and ER analyses are being used to simulate CD20-TCB dosing regimens that maximize efficacy and mitigate CRS risk, including fixed and step-up dosing regimens. Conclusions: PopPK and E-R relationships are characterized for the novel CD20/CD3 TCB antibody CD20-TCB and are being used to support optimal biological-dose selection as a single agent in ongoing combination investigations (Morschhauser et al. ASH 2019; Hutchings et al. ASH 2019). Disclosures Djebli: F. Hoffmann-La Roche Ltd: Employment. Jaminion:F. Hoffmann-La Roche Ltd: Employment. Laurent:F. Hoffmann-La Roche Ltd: Employment. Mercier:F. Hoffmann-La Roche Ltd: Employment. Kratochwil:F. Hoffmann-La Roche Ltd: Employment. Bröske:Roche: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Moore:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. Morcos:Roche: Employment, Equity Ownership. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding ('Fab') regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.
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Shi, Rong, Tong Lu, Grace Ku, Hao Ding, Tomohisa Saito, Leonid Gibiansky, Priya Agarwal, et al. "Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma." Cancer Chemotherapy and Pharmacology 86, no. 3 (August 8, 2020): 347–59. http://dx.doi.org/10.1007/s00280-020-04119-8.
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Abstract Purpose The CD79b-targeted antibody–drug conjugate polatuzumab vedotin (pola), alone and with chemoimmunotherapy, has clinical efficacy and a tolerable safety profile in B-cell non-Hodgkin lymphoma (B-NHL). We assessed (a) whether exposure from global studies of pola is comparable to Asian patients, and (b) if the recommended pola dose is appropriate in Asian patients based on exposure. Methods The pharmacokinetics (PK) of pola in Asian and global populations was characterized for three analytes (antibody-conjugated monomethyl auristatin E (MMAE) [acMMAE], total antibody, and unconjugated MMAE) in five phase 1b/2 single-agent and combination studies in B-NHL patients (JO29138 [JAPICCTI‐142580], DCS4968g [NCT01290549], GO27834 [NCT01691898], GO29044 [NCT01992653], and GO29365 [NCT02257567]). PK data were compared between Japanese phase 1 JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies and between Asian and non-Asian patients in the randomized relapsed/refractory B-NHL cohorts of the phase 1b/2 study GO29365 (NCT02257567). A population PK (popPK) model was used to assess the effects of Asian race and region on acMMAE and unconjugated MMAE exposure. Results PK non-compartmental analysis (NCA) parameters for the key analyte acMMAE in the Japanese JO29138 (JAPICCTI‐142580) and global phase 1 DCS4968g (NCT01290549) studies were similar. In GO29365 (NCT02257567), the phase 1b/2 combination study, mean exposure to the analytes was generally lower in Asian patients (by ~ 9.9 to 17.5%), but not to a clinically meaningful extent. Overall, the popPK model further suggested comparable PK in Asian patients with B-NHL (race or region) versus non-Asian patients. Conclusion Race has no clinically meaningful effect on pola PK. These results (and observations from efficacy/safety exposure–response analyses) support no pola dose adjustments are warranted for Asian patients with DLBCL.
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Holford, N. H., I. Mathews, and C. Kirkpatrick. "Quantitative basis for aminoglycoside (AG) target concentration intervention from a population pharmacokinetic model (POPPK)." Clinical Pharmacology & Therapeutics 73, no. 2 (February 2003): P57. http://dx.doi.org/10.1016/s0009-9236(03)90567-4.
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Soy, D., E. Aldasoro, L. Guerrero, E. Posada, N. Serret, T. Mejía, J. A. Urbina, and J. Gascón. "Population Pharmacokinetics of Benznidazole in Adult Patients with Chagas Disease." Antimicrobial Agents and Chemotherapy 59, no. 6 (March 30, 2015): 3342–49. http://dx.doi.org/10.1128/aac.05018-14.
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ABSTRACTThe aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h;V/F, 89.6 liters; andKa, 1.15 h−1). No covariates were found to be significant for CL/FandV/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011-002900-34 and at ClinicalTrials.gov under number NCT01755403.)
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Haanen, John B. A. G., Joanna C. Masters, Bo Huang, Toni K. Choueiri, Robert J. Motzer, Akash Khandelwal, Haiqing (Isaac) Dai, et al. "Avelumab flat dose regimen: Justification for use in advanced renal cell carcinoma (aRCC)." Journal of Clinical Oncology 38, no. 5_suppl (February 10, 2020): 32. http://dx.doi.org/10.1200/jco.2020.38.5_suppl.32.
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32 Background: Avelumab, an anti–PD-L1 monoclonal antibody, was recently approved for the treatment of aRCC in combination with axitinib and was previously indicated for the treatment of metastatic Merkel cell carcinoma (MCC) and platinum-treated advanced/metastatic urothelial carcinoma (UC). Although avelumab was approved with weight-based dosing (10 mg/kg intravenously [IV] every 2 weeks [Q2W]), it was subsequently approved for flat dosing (800 mg IV Q2W) based on population pharmacokinetic (popPK), exposure-efficacy and exposure-safety modeling and simulations in MCC and UC (Novakovic AM, et al. Clin Pharmacol Ther. 2019). The justification for the recommended flat-dose regimen for avelumab as combination therapy with axitinib in aRCC is presented. Methods: Simulated exposure metrics (eg, area under the curve) from the previous popPK model (data from 1,827 patients with solid tumors across 3 clinical trials) for both weight-based and flat-dose regimens were compared with the exposure metrics obtained from treatment-naive patients with aRCC enrolled in 2 clinical studies (N = 488 from NCT02493751 and NCT02684006) who received avelumab (10 mg/kg Q2W) + axitinib (5 mg orally twice daily). Avelumab exposure-response relationships for safety and efficacy were also analyzed. Endpoints included grade ≥3 treatment-emergent adverse events (TEAEs), any-grade infusion-related reactions (IRRs) and immune-related (ir)AEs, and progression-free survival (PFS) by independent review. Results: The administration of weight-based dosing of avelumab in the aRCC population yielded similar PK exposures to simulated reference exposures of the flat-dose regimen in the solid tumor population. Avelumab exposure was not associated with increased probabilities of grade ≥3 TEAEs or IRRs, although there was a weak association with an increased probability of any-grade irAEs. Conclusions: The similar exposures observed for both avelumab dosing regimens in aRCC, and in prior studies in the MCC and UC populations, suggest that the 800 mg Q2W flat-dose regimen will maintain the benefit-risk ratio for avelumab + axitinib for treatment-naive patients with aRCC. Clinical trial information: NCT02493751 . Clinical trial information: NCT02684006.
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Djebli, Nassim, Peter N. Morcos, Félix Jaminion, Elena Guerini, Nicole A. Kratochwil, Nicole Justies, Eginhard Schick, et al. "Population Pharmacokinetics and Exposure-Response Analyses for Glofitamab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL): Confirmation of Efficacy and CRS Mitigation in Patients with Step-up Dosing." Blood 136, Supplement 1 (November 5, 2020): 1–2. http://dx.doi.org/10.1182/blood-2020-136311.
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Introduction: Glofitamab (RG6026; RO7082859; CD20-TCB) is a novel '2:1' format T-cell-engaging bispecific antibody that has two CD20 and one CD3 binding domains, enabling increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing in B-cell malignancies. Clinical data from NP30179 demonstrated that fixed dosing of glofitamab (0.6-25mg) induced high and durable complete responses with a manageable safety profile in heavily pre-treated R/R NHL patients (pts; Dickinson, et al. EHA 2020). Obinutuzumab pretreatment (Gpt) 7 days prior to first administration of glofitamab was shown to be effective in mitigating the risk of cytokine release syndrome (CRS), allowing for rapid escalation of glofitamab to clinically active doses (Dickinson, et al. EHA 2020). We previously investigated population pharmacokinetics (popPK) and exposure-response (ER) relationships for glofitamab in NP30179; NCT03075696 (Djebli N, et al. Blood 2019), where modelling indicated step-up dosing would further mitigate CRS while maximizing efficacy. The present analysis is an update of previous models, including confirmatory data from the first step-up dosing (SUD) pts. Methods: Pts with indolent (i) or aggressive (a) R/R NHL received glofitamab fixed dosing (0.005-25mg every 2 or 3 weeks) or SUD (n=31, 2.5/10/16 and 2.5/10/30mg) following single Gpt 1000mg on Cycle (C) 1 Day (D) −7 to mitigate CRS. Serial and sparse glofitamab, and sparse G PK data were used to develop a popPK model in NONMEM® software (v7.4). The cut-off date of April 17, 2020 enabled inclusion of 16 (2.5/10/16mg) and 15 (2.5/10/30mg) SUD pts. Physiologically relevant covariates were investigated for their potential influence on glofitamab PK variability. Using the established G popPK model (Gibiansky, et al. CPT Pharmacometrics Syst Pharmacol 2014), G concentration-time profiles were constructed to estimate glofitamab receptor occupancy (RO%) in the presence of G competing for CD20 receptors over time. The relationship between glofitamab AvgRO% over the first 24 hours and CRS, with a focus on Grade (Gr) ≥2 CRS (defined by ASTCT criteria [Lee, et al. 2019]) was investigated in iNHL and aNHL pts combined. ER relationships between glofitamab time-averaged RO% (AvgRO%) up to C3D1, which is when the first response assessment was taken, and complete response rate (CRR) were characterized in aNHL pts who reached C3D1. Results : PopPK were analyzed in 230 iNHL and aNHL pts with ≥1 PK sample (fixed and SUD). ER relationships were analyzed in 95 aNHL pts with PK/efficacy data at C3D1, and in 204 iNHL and aNHL pts with PK/safety data. Glofitamab PK were best described using a two-compartment PK model with linear clearance and were comparable in pts with iNHL and aNHL. The effect of bodyweight on volumes and clearances was retained. Positive ER relationships were observed between AvgRO% over the first 24 hours and Gr ≥2 CRS in both iNHL and aNHL pts (p=0.002; Figure 1A), and between AvgRO% up to C3D1 and efficacy in aNHL pts (p=0.008; Figure 1B). Based on previous ER analyses (Djebli, et al. Blood 2019) of data from pts receiving fixed dosing, a SUD regimen (2.5/10/30mg Q3W) was selected to optimize the benefit/risk profile by beginning treatment at a dose to have CRS at manageable levels whilst allowing escalation to a higher dose associated with better clinical response. Updated ER analysis from fixed (n=199) and SUD (n=31) pts predicts an AvgRO% in the first 24 hours of 0.16% (0.10-0.29%), corresponding to a predicted Gr ≥2 CRS rate of 23.3% (20.8-26.8%) in iNHL and aNHL pts, and an AvgRO% to C3D1 of 0.75% (0.49-1.98%) corresponding to an anticipated CRR at Cycle 3 of 46.1% (42.7-53.8%) in aNHL pts. In comparison, clinical data from aNHL and iNHL pts receiving 2.5/10/16 and 2.5/10/30mg SUD (Hutchings, et al. ASH 2020) demonstrated a Gr ≥2 CRS rate of 21.6 % following the 2.5mg glofitamab dose (n=37), and a complete metabolic response rate of 40.6% (n=32). Conclusions: Glofitamab PopPK and ER relationships for efficacy/safety were updated, including data from SUD pts. These models and emerging SUD clinical data confirm that in NHL pts, the SUD regimen allowed glofitamab escalation up to 30mg to maximize efficacy while minimizing the risk of increased CRS at the first administration. These models are being developed further to support optimal biological-dose selection of glofitamab, both as monotherapy and in combination with other agents. Disclosures Djebli: F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Morcos:F. Hoffmann-La Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Jaminion:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Guerini:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company. Kratochwil:F. Hoffmann-La Roche: Current Employment. Justies:F. Hoffmann-La Roche: Current Employment. Schick:F. Hoffmann-La Roche: Current Employment. Kwan:Genentech, Inc./ F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Humphrey:F. Hoffmann-La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Lundberg:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Carlile:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. OffLabel Disclosure: Glofitamab (RG6026; CD20-TCB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.
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Chelle, Pierre, Cindy Yeung, Santiago Bonanad Boix, Juan Cristobal Morales, Margareth C. Ozelo, Juan E. Megias Vericat, Alfonso Iorio, Jeffrey Spears, Roser Mir, and Andrea N. Edginton. "Creating a Population Model for PK-Tailored Dosing Using Real-World Data from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) Platform." Blood 132, Supplement 1 (November 29, 2018): 1191. http://dx.doi.org/10.1182/blood-2018-99-115308.
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Abstract Objective: The Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) platform allows hemophilia treaters to estimate individual PK parameters for clotting factor concentrates using only a few blood samples drawn from their patients. Population pharmacokinetic (PopPK) models used with WAPPS-Hemo are usually built using clinical trial data provided by drug manufacturers. These trials can be restrictive with respect to patient covariates such as age and body weight. On the other hand, real-world pharmacokinetic data submitted to WAPPS captures the breadth of hemophilia patients. We tested the use of post-infusion clotting factor concentrate measurements collected through routine use of WAPPS-Hemo to develop a plasma-derived FVIII (Fanhdi/Alphanate)-specific model for which no trial data was available. Methods: Plasma factor activity measurements and information on hemophilia A patients were extracted from the WAPPS database. PopPK modeling was completed in NONMEM (ver 7.3, Icon, PLC). Evaluation of model-based Bayesian forecasting to derive the individual PK parameters included 10-fold internal cross validation, limited sampling analysis, and external validation using WAPPS data collected subsequently. The ability of the model to capture age related changes in PK was assessed through separate examination of predictive accuracy for children ≤ 12 yrs and for children and adults >12 yrs of age. Results: Post-infusion FVIII activity levels from 92 patients were used to derive and internally validate the model. Two-thirds of the patients originated from three centres (Campinas, Brazil; Valencia, Spain; and Santiago, Chile) with the remaining patients from 9 other WAPPS centers. Patients were 1-71 yrs (~33.7% ≤12 yrs) with a body weight range between 9 and 119 kg. Each patient provided between 1-8 activity levels up to 72 hours post infusion (386 data points in total). The final PopPK model followed 2-compartment kinetics with fat-free mass and age as covariates. Clearance was consistent across age until 25 years where clearance declined. The ability of the model to capture the PK in children ≤ 12 yrs was similar in accuracy to patients >12 yrs (Figure 1). Limited sampling analysis demonstrated that sampling strategies using two to three samples with one sample being a 72 hour post-infusion sample produced time-above-2% activity estimates, on average, <5% different than a sampling strategy using 16 post-infusion samples. Bayesian forecasting with additional WAPPS data collected following the model development process (n=10 patients) demonstrated that half-life, clearance, central volume and time-above-2% estimates were within those of the original patient population. Conclusions: Use of routine clinical care data for model development was feasible and expanded the covariate space (e.g. age) from what is traditionally included in trials. A promising approach would be to supplement clinical trial data with routine clinical data in order to build future PopPK models. On one hand, dense data from clinical trials brings stability to the model and provides a good description of the PK curve and may reduce random error if measured in a central lab; on the other hand, sparse data from routine practice widens the possible observations, inputs and covariates of the model, and could better perform the scope of individual Bayesian forecasting. Our analysis has demonstrated that collecting a few real world samples per patient not only allows accurately determining individual PK parameters, but was also effective for developing a model for a specific brand. This research was supported by Grifols, a manufacturer of plasma-derived FVIII/VWF concentrates. The WAPPS-Hemo team independently performed the derivation and validation of the model. All authors reviewed and approved the abstract as submitted. Disclosures Ozelo: BioMarin: Honoraria, Speakers Bureau; Grifols: Honoraria; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Honoraria, Research Funding. Iorio:Shire: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Shire; Pfizer: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Pfizer; NovoNordisk: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Novo Nordisk; Grifols: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Grifols; Octapharma: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Octapharma; CSL: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with CSL; Bayer: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Bayer; Roche: Other: Alfonso Iorio's Institution has received project based funding via research or service agreements with Roche. Spears:Grifols: Employment. Mir:Grifols: Employment. Edginton:Bayer: Honoraria.
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Ceglie, Teresa, Berardino Pollio, Irene Ricca, Maria Messina, Claudia Linari, and Mauro Pagliarino. "Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products." Blood 134, Supplement_1 (November 13, 2019): 1123. http://dx.doi.org/10.1182/blood-2019-132199.
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Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.
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Ji, Shuangmin, Dewei Shang, Kehua Wu, Anning Li, Xiwei Li, Chenhui Deng, Liang Li, Tianyan Zhou, Chuanyue Wang, and Wei Lu. "Population pharmacokinetic-pharmacodynamic (PopPK/PD) modeling of risperidone and its active metabolite in Chinese schizophrenia patients." Int. Journal of Clinical Pharmacology and Therapeutics 54, no. 05 (May 1, 2016): 378–89. http://dx.doi.org/10.5414/cp202498.
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Nguyen, Linh Thuy, Sunny Chapel, Tim Meyer, Ann-Lii Cheng, Anthony B. El-Khoueiry, Robin Kate Kelley, Ghassan K. Abou-Alfa, and Steven Lacy. "Integrated population pharmacokinetic (PopPK) modeling of cabozantinib (C) in patients (pts) with various cancer types including hepatocellular carcinoma (HCC)." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 305. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.305.
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305 Background: C significantly improved overall survival vs placebo in pts with previously treated advanced HCC in the phase 3 CELESTIAL trial (NCT01908426). In a previous single dose PK study, increased C exposure was observed in healthy volunteers (HV) with mild or moderate hepatic impairment (Nguyen, J Clin Pharmacol, 2016). An integrated PopPK model was recently developed to characterize C concentration data from HV and pts with various cancers, including renal cell carcinoma, castration-resistant prostate cancer, and medullary thyroid cancer (MTC) (Lacy, Cancer Chemother Pharmacol, 2018). Here, we update the model to include data for pts with advanced HCC from CELESTIAL and a prior phase 2 trial. Methods: The updated PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated data from 10 clinical studies with 9510 measurable C concentrations from 2023 subjects, including 489 pts with advanced HCC. Eligible pts with HCC were Child-Pugh class A. Evaluated covariates included age, gender, race, body weight, cancer type, and liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG). Results: Overall, 70% of pts had normal hepatic function by NCI-ODWG criteria; 28% had mild, 1% had moderate, and <1% had severe hepatic dysfunction. A 2-compartment model with first-order elimination and dual first- and zero-order absorption processes adequately described the data. As in the previous model, the MTC population was the only cancer type to have a notable difference in C PK, with ~90% increase in apparent clearance (CL/F) versus HV and pts with other cancers including HCC. For a White male, CL/F was estimated as 2.48 L/hr and apparent volume of the central compartment (Vc/F) as 212 L. Inter-individual variability was ~46% for CL/F and ~67% for Vc/F. Other demographic covariates were predicted to have a small to moderate impact on C CL/F. Liver dysfunction, per NCI-ODWG criteria, had no discernable effect on C CL/F. Conclusions: C exposure at an equivalent daily dose is predicted to be similar in pts with several cancer types including advanced HCC with mild liver dysfunction.
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Gulley, James L., David R. Spigel, Karen Kelly, Joseph Aisner, Vikram K. Chand, Andre Koenig, Hugues Dolgos, Shaonan Wang, and Claire F. Verschraegen. "Exposure-response and PD-L1 expression analysis of second-line avelumab in patients with advanced NSCLC: Data from the JAVELIN Solid Tumor trial." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9086. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9086.
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9086 Background: Avelumab is a fully human anti‒PD-L1 IgG1 antibody showing promising efficacy and safety in patients (pts) with non-small cell lung cancer (NSCLC) and other tumors. Here, we present exposure–response (E–R) and PD-L1 expression analyses of second-line (2L) avelumab treatment in pts with NSCLC from a phase 1 trial (NCT01772004). Methods: Pts with NSCLC received 2L avelumab 10 mg/kg IV every 2 weeks (Q2W) until progression or unacceptable toxicity. Serum samples were taken at various time points for pharmacokinetic (PK) analysis. Trough concentrations after first dose (Ctroughfirst-dose) were predicted using an identified linear 2-compartment population PK (popPK) model without covariates other than pt body weight. Objective response rate (ORR) was evaluated (RECIST v1.1), and correlated with tumor cell (TC) PD-L1 expression (clone 73-10). Pooled safety data from various tumors in the large phase 1 trial were assessed. Results: In 184 avelumab-treated pts, unselected for PD-L1 expression, ORRs were 8.7%, 10.9%, 19.6%, and 17.4% for increasing quartiles of Ctroughfirst-dose (Q1–4). Using ≥1%, ≥5%, ≥50%, and ≥80% PD-L1 staining cutoffs, pts in the upper half of exposure (Ctroughfirst-dose Q3–4 [n = 92]), had ORRs of 25% (n = 59), 26% (n = 39), 33% (n = 21), and 43% (n = 14), respectively. Higher avelumab exposure was associated with a modest increase in immune-related adverse events (irAEs). PopPK modeling suggested Ctroughfirst-dose could be optimally increased with alternate avelumab dosing (10 mg/kg weekly vs Q2W, or 20 mg/kg Q2W [simulated median Ctroughfirst-dose 48 μg/mL vs 18 μg/mL, or 36 μg/mL]). Conclusions: Avelumab has shown clinical activity and acceptable safety in multiple tumors similar to other agents in class. Preliminary analysis of a cohort of pts with 2L advanced NSCLC shows a trend for higher ORR with increasing avelumab Ctroughfirst-dose quartiles and with higher levels of TC PD-L1 expression. Although this apparent E–R observation may be confounded by single-dose testing or other factors, this analysis provides rationale for studies of more intensive avelumab dosing regimens to assess further clinical benefit in pts with advanced NSCLC. Clinical trial information: NCT01772004.
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Riccobene, Todd, T. J. Carrothers, ScD, William Knebel, Susan Raber, and Phylinda L. S. Chan. "1567. Pharmacokinetic/Pharmacodynamic Target Attainment in Adult and Pediatric Patients following Administration of Ceftaroline Fosamil as a 5-Minute Infusion." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S572—S573. http://dx.doi.org/10.1093/ofid/ofz360.1431.
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Abstract Background Ceftaroline fosamil is approved in the United States for treating patients ≥2 months old with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, and for similar indications in Europe. The active metabolite, ceftaroline, has in vitro activity against common Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae. Population pharmacokinetic (popPK) modeling and simulation were used to assess systemic exposure and PK/pharmacodynamic (PK/PD) target attainment for S. aureus and S pneumoniae for 5- and 60-minute infusions. Methods A simultaneous popPK model, including 2 compartments each, for ceftaroline fosamil and ceftaroline was previously developed using an extensive database of adult and pediatric data. An effect of renal function maturation as a function of postmenstrual age was included on ceftaroline clearance for children <2 years. This model was used to conduct simulations for-approved ceftaroline doses administered as 5- and 60-min infusions to adult and pediatric patients with normal renal function and mild renal impairment. For adults, 100 simulations of 300 patients each were performed for each dose regimen, and covariates were generated from a multivariate normal distribution using covariate correlations from observed data. For pediatric patients, 100 simulations were performed for each dose regimen with 600 patients in each 1-month age group. Weights for pediatric age groups were based on CDC growth charts. Results The median proportion of simulated patients with normal renal function achieving %fT>MIC targets of 35% and 44% (associated with 1-log kill of S. aureus and S pneumoniae, respectively), are shown for 5- and 60-min infusions (figure). PK/PD target attainment was similar for both infusion times and was >99% at an MIC of 1 mg/L for S. aureus and an MIC of 0.5 mg/L for S pneumoniae. Ceftaroline AUC was similar for both infusion times, and Cmax was approximately 30%–40% higher for the 5-min infusion. Conclusion Ceftaroline fosamil gave as a 5-min infusion to adult and pediatric patients ≥2 months of age achieved similar PK/PD target attainment as a 60-min infusion for S. aureus and S pneumoniae for MICs up to 1 mg/L and 0.5 mg/L, respectively. Disclosures All authors: No reported disclosures.
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Barth, Aline, Cindy l. Mininger, Thomas Lewandowski, Mohammad Hossain, Stephen Rittenhouse, and Jennifer Hoover. "1560. Pharmacokinetics–Pharmacodynamics (PK-PD) of Gepotidacin (GEP) Against Escherichia coli in Murine Pyelonephritis and Thigh Infection Models." Open Forum Infectious Diseases 6, Supplement_2 (October 2019): S569. http://dx.doi.org/10.1093/ofid/ofz360.1424.
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Abstract Background GEP, a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens implicated in a range of infections, including drug-resistant strains of E. coli associated with acute cystitis. Methods PK and PD studies were conducted in murine (male CD-1 mice) thigh and kidney infections. The administered doses ranged from 1 to 200 mg/kg SC every 6 hours starting 1-hour post-infection. Infected tissues were evaluated for bacterial burden at 24-h post-infection (baseline controls at 1-hour post-infection). Plasma and tissue samples (kidney or thigh homogenates) were collected at 15, 30, 60, 120, 240 and 360 minutes. A population PK (PopPK) model was built in NONMEM using plasma exposures. Efficacy was determined against E. coli ALL, 997577, ATCC25922, IR5 and NCTC13441 (MICs of 1 to 4 µg/mL) in thigh-infected neutropenic (I-) mice and against E. coli ALL in kidney-infected immunocompetent (I+) and I- mice. The PopPK model was used to determine GEP exposures associated with efficacy. PK-PD analyses were conducted using Phoenix WinNonLin 6.3 (Pharsight). The change in log10 colony-forming units (CFU) from baseline were correlated with free drug (f) AUC:MIC using an inhibitory model from the Phoenix library, and model parameter values for each isolate were used to calculate the plasma fAUC:MIC associated with stasis, 1- or 2-log10 reductions in CFU. Results Plasma PK data were best fit by a 1-compartment IV model with first-order elimination and were similar in I+ vs. I- and thigh- vs. kidney-infected mice. The AUC0-6 of GEP in kidney was approximately 4- to 5-fold higher than in plasma while the AUC0-6 in thigh was approximately half of plasma. In the I- thigh model, median plasma fAUC:MIC ratios for stasis, 1- or 2-log10 reductions in CFU were 11, 16, and 25 (ranges 3–17, 4–25 and 7–40), respectively. Efficacy vs. E. coli ALL was similar in I- mice infected in thigh or kidney. In I+ mice, the PK-PD target was reduced by half. Conclusion Median plasma fAUC:MIC targets ranged from 11 to 25. Higher drug levels in kidney vs. plasma or thigh did not translate into improved efficacy in pyelonephritis vs. thigh-infection models. Disclosures All authors: No reported disclosures.
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Williams, Grant Richard, Mustafa Al-Obaidi, Joseph Rower, Christian Harmon, Chen Dai, Edward Acosta, Smith Giri, et al. "Does oxaliplatin pharmacokinetics (PKs) explain associations between body composition and chemotherapy toxicity risk in older adults with gastrointestinal (GI) cancers?" Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3095. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3095.
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3095 Background: Considerable inter-individual variability in oxaliplatin toxicity exists in older adults with GI cancers. Low lean body mass (LBM), commonly known as sarcopenia, influences toxicity and is not incorporated in standard body surface area-based dosing, which may affect oxaliplatin PK and tolerability, but has not been examined systematically. Methods: We examined oxaliplatin PK in 26 older adults (103 concentrations) with GI cancers (NCT03998202). Using the transverse section at L3, skeletal muscle area (SMA) and total adipose tissue (TAT) were quantified (Slice-O-Matic software) and LBM was calculated (LBM = 0.30 × SMA + 6.06). Noncompartmental methods (WinNonlin 7.0) were used for PK estimates and a one compartment population PK model (PopPK) was developed. Covariates included age, sex, LBM, TAT, weight, BMI, creatinine clearance, BSA, serum albumin, and body composition phenotypes (i.e. low LBM-high TAT, etc.). Results: Median age was 68yrs, 69% male, 88% white, and mostly colorectal (62%) and pancreatic (27%) cancers. There was wide variability in oxaliplatin volume of distribution (Vd: 12.5-259L), peak concentrations (Cmax: 404-3642ng/mL), and clearance (CL: 26.7-270L/hr). Participants with lower LBM had lower Vd (r = 0.51, p< 0.01); those with higher TAT had higher Cmax (r = 0.53, p< 0.01). Higher albumin was associated with lower Cmax (r = -0.49, p= 0.01) and higher CL (r = 0.47, p= 0.01). The phenotype of low LBM + high TAT had the lowest Vd (Relative Risk [RR] 0.32, p= 0.01), lowest CL (RR 0.39, p< 0.01), and highest Cmax (RR 3.3, 95% CI 1.7-6.5, p< 0.01). Eleven patients (44%) had grade 3-5 chemotoxicity. Vd (r = -0.46, p= 0.02) and Cmax (r = 0.44, p= 0.03) were associated with grade 3-5 chemotoxicity. The phenotype of low LBM + high TAT was associated with a 45% higher risk of grade 3-5 chemotoxicity (RR = 1.45, 95% CI 1.1-2.1, p= 0.04), while BSA was not (r = -0.04, p= 0.9). In the popPK model, body composition was associated with PK (TAT with Vd [p = 0.006] and CL [p < 0.001]), as was albumin (Vd p = 0.004; CL p = 0.002), while BSA was not (Vd p = 0.08; CL p = 0.2). Compared to BSA, an additional 11-17% in oxaliplatin PK variability was explained by LBM (11%), TAT (14%), and albumin (17%). Conclusions: Relationships between body composition, oxaliplatin PK, and severe chemotoxicity suggest the need for novel dosing strategies that incorporate body composition to reduce chemotoxicity and improve outcomes. Clinical trial information: NCT03998202.
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Suri, A., D. R. Mould, G. Song, J. Kinley, and K. Venkatakrishnan. "BRENTUXIMAB VEDOTIN POPULATION PHARMACOKINETIC (POPPK) MODELLING IN ADULT AND PAEDIATRIC PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) HEMATOLOGIC MALIGNANCIES." Hematological Oncology 37 (June 2019): 524–25. http://dx.doi.org/10.1002/hon.209_2631.
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Gangadhar, Tara C., Janice Mehnert, Amita Patnaik, Omid Hamid, Matteo S. Carlino, F. Stephen Hodi, Christian U. Blank, et al. "Population pharmacokinetic (popPK) model of pembrolizumab (pembro; MK-3475) in patients (pts) treated in KEYNOTE-001 and KEYNOTE-002." Journal of Clinical Oncology 33, no. 15_suppl (May 20, 2015): 3058. http://dx.doi.org/10.1200/jco.2015.33.15_suppl.3058.
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Ou, Ying, Kun Wang, Lucy Liu, Ashutosh Jindal, Yuying Gao, and Sri Sahasranaman. "Exposure-Response Relationship of the Bruton Tyrosine Kinase Inhibitor, Zanubrutinib (BGB-3111) in Patients with Hematologic Malignancies." Blood 134, Supplement_1 (November 13, 2019): 5063. http://dx.doi.org/10.1182/blood-2019-129580.
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Background: Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible inhibitor of Bruton tyrosine kinase (BTK), currently in phase 3 development for the treatment of hematologic malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM). In a dose escalation study evaluating doses of 40, 80, 160, and 320 mg once daily and 160 mg twice daily, no dose limiting toxicities were observed and maximum tolerated dose (MTD) was not established. Objective responses have been observed in patients with various B-cell malignancies (including CLL, MCL, WM) at all tested dose levels. In phase 1 testing, high plasma concentrations were achieved, resulting in complete and sustained 24-hour BTK inhibition in blood and lymph nodes in patients treated at 160 mg twice daily (Tam et al. Blood 2016;128:642). To support dose selection, this exposure-response (E-R) analysis evaluated exposure-safety and exposure-efficacy (in MCL) relationships in patients with B-cell malignancies receiving zanubrutinib monotherapy. Methods: A population pharmacokinetic (PopPK) model was developed from 600 subjects enrolled in 9 clinical studies in patients with B-cell malignancies and healthy volunteers. Exposure data such as steady-state area under the plasma concentration time curve (AUC0-24,ss), maximum observed plasma concentration (Cmax ) or steady state trough concentration (Cmin) derived from the PopPK analysis were used in the E-R analysis. Exposure-efficacy analyses were performed using exposure metrics and overall response rate (ORR) data from two studies in patients with relapsed/refractory (R/R) MCL (n=51), including Study 206, a pivotal Phase 2 study conducted in China and study AU-003, a global Phase 1, dose escalation/cohort expansion study. The efficacy endpoint evaluated was ORR, as assessed by an independent review committee (IRC) as well as by investigators, according to 2014 Lugano Classification. Exposure-safety analyses were conducted using data from 4 studies in patients with B-cell malignancies (n=372) receiving zanubrutinib as monotherapy at a total daily dose from 40 mg to 320 mg. The safety endpoints evaluated included Grade ≥ 3 adverse events (AE) and AEs of interests, including neutropenia, thrombocytopenia, anemia, infections/infestations, all events of secondary primary malignancies, all events of atrial fibrillation and flutter, major bleeding events, and any bleeding events. Results: PopPK analysis demonstrated that race, body weight, age, CrCL, sex, tumor type, and use of acid-reducing agents did not show a statistically significant impact on the PK of zanubrutinib. The PK profile of zanubrutinib was comparable between Asians and non-Asians, which allows for bridging of clinical efficacy and safety data across the pivotal studies conducted globally (AU-003) and in China (206). The analysis showed that the median AUC0-24,ss and Cmax values were 1736 ng·h/mL and 275 ng/mL in responders compared with 1326 ng·h/mL and 175 ng/mL in nonresponders, respectively. Although overall median exposure (AUC0-24,ss, Cmax) was higher in responders compared with nonresponders, no significant E-R relationship was identified for efficacy based on probability of observing ORR and logistic regression model (Fig 1). The E-R relationships based on investigator assessments were consistent with those based on IRC assessments. For the exposure-safety analysis, the exposure ranges were similar in patients experiencing adverse events of interests relative to those who were not. There were no evident E-R relationships between PK exposure (AUC0-24,ss, Cmax, or Cmin) and the probability to have adverse events of interest (eg., Fig. 2). Conclusion: E-R analyses indicate that higher plasma exposures of zanubrutinib were not associated with higher probability to have adverse events across the dose range of 40 mg to 320 mg in patients with B-cell malignancies. This result supports the recommended dose of 160 mg twice daily in patients with MCL, based on high rates of objective response in patients with R/R MCL, generally favorable safety and tolerability profiles, and complete and sustained BTK occupancy in PBMCs and target tissues at this dose. Disclosures Ou: BeiGene: Employment. Jindal:BeiGene: Employment. Sahasranaman:BeiGene: Employment, Equity Ownership.
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Mohanan, E., J. C. Panetta, K. M. Lakshmi, E. S. Edison, A. Korula, N. A. Fouzia, A. Abraham, et al. "Population pharmacokinetics of fludarabine in patients with aplastic anemia and Fanconi anemia undergoing allogeneic hematopoietic stem cell transplantation." Bone Marrow Transplantation 52, no. 7 (May 8, 2017): 977–83. http://dx.doi.org/10.1038/bmt.2017.79.
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Abstract Although hematopoietic stem cell transplantation (HSCT) with a conditioning regimen consisting of fludarabine (F-araA) and cyclophosphamide (Cy) is associated with improved outcome in young patients with aplastic anemia (AA) and Fanconi anemia (FA), several factors limit the success of the procedure. We evaluated the population pharmacokinetics (POPPK) of F-araA and its influence on HSCT outcome in patients (n=53) with AA and FA undergoing HSCT. Patients carrying a 5′-UTR polymorphism in NT5E gene (rs2295890 G>C) exhibited significantly lower plasma F-araA clearance compared to those with wild-type genotype (7.12 vs 5.03 L/h/m2 (29%) P<0.05). F-araA clearance was significantly higher in patients with AA compared to FA (2.46 ×, P<1e−6). Of all the outcome parameters evaluated (engraftment, rejection/graft failure, GvHD, TRM, OS), high F-araA AUC (>29.4 μm*h) was the only significant factor associated with the development of aGvHD by both univariate and multivariate analysis (P=0.02). The influence of plasma F-araA levels need to be evaluated in a larger cohort of patients to propose the need for therapeutic drug monitoring.
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Würthwein, Gudrun, Oliver A. Cornely, Mirjam N. Trame, Janne J. Vehreschild, Maria J. G. T. Vehreschild, Fedja Farowski, Carsten Müller, et al. "Population Pharmacokinetics of Escalating Doses of Caspofungin in a Phase II Study of Patients with Invasive Aspergillosis." Antimicrobial Agents and Chemotherapy 57, no. 4 (January 18, 2013): 1664–71. http://dx.doi.org/10.1128/aac.01912-12.
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ABSTRACTCaspofungin (CAS) is approved for second-line management of proven or probable invasive aspergillosis at a dose of 50 mg once daily (QD). Preclinical and limited clinical data support the concept of the dose-dependent antifungal efficacy of CAS with preservation of its favorable safety profile. Little is known, however, about the pharmacokinetics (PKs) of higher doses of CAS in patients. In a formal multicenter phase II dose-escalation study, CAS was administered as a 2-h infusion at doses ranging from 70 to 200 mg QD. CAS PK sampling (n= 468 samples) was performed on day 1 and at peak and trough time points on days 4, 7, 14, and 28 (70 mg,n= 9 patients; 100 mg,n= 8 patients; 150 mg,n= 9 patients; 200 mg,n= 20 patients; total,n= 46 patients). Drug concentrations in plasma were measured by liquid chromatography tandem mass spectroscopy. Population pharmacokinetic analysis (PopPK) was performed using NONMEM (version 7) software. Model evaluation was performed using bootstrap analysis, prediction-corrected visual predictive check (pcVPC), as well as standardized visual predictive check (SVPC). The four investigated dose levels showed no difference in log-transformed dose-normalized trough levels of CAS (analysis of variance). CAS concentration data fitted best to a two-compartment model with a proportional-error model, interindividual variability (IIV) fitted best on clearance (CL), central and peripheral volume of distribution (V1andV2, respectively) covariance fitted best on CL andV1, interoccasion variability (IOV) fitted best on CL, and body weight fitted best as a covariate on CL andV1(CL, 0.411 liters/h ± 29% IIV; IOV on CL, 16%;V1, 5.785 liters ± 29% IIV; intercompartmental clearance, 0.843 liters/h;V2, 6.53 liters ± 67% IIV). None of the other examined covariates (dose level, gender, age, serum bilirubin concentration, creatinine clearance) improved the model further. Bootstrap results showed the robustness of the final PopPK model. pcVPC and SVPC showed the predictability of the model and further confirmed the linear PKs of CAS over the dosage range of 70 to 200 mg QD. On the basis of the final model, geometric mean simulated peak plasma levels at steady state ranged from 13.8 to 39.4 mg/liter (geometric coefficient of variation, 31%), geometric mean trough levels ranged from 4.2 to 12.0 mg/liter (49%), and geometric mean areas under the concentration-time curves ranged from 170 to 487 mg · h/liter (34%) for the dosage range of 70 to 200 mg QD. CAS showed linear PKs across the investigated dosage range of 70 to 200 mg QD. Drug exposure in the present study population was comparable to that in other populations. (This study has been registered with the European Union Drug Regulating Authorities Clinical Trials website under registration no. 2006-001936-30 and at ClinicalTrials.gov under registration no. NCT00404092.)
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Kantasiripitak, W., R. Mathôt, B. Oldenburg, A. Buisson, M. Ferrante, D. Laharie, G. D’Haens, S. Vermeire, and E. Dreesen. "P497 The value of endoscopic healing index monitoring for guiding infliximab dosing in patients with Crohn’s disease." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S481—S483. http://dx.doi.org/10.1093/ecco-jcc/jjab076.620.
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Abstract Background The endoscopic healing index (EHI) is a novel multi-protein serum biomarker test developed and validated to assess endoscopic disease activity in patients with Crohn’s disease (CD). Evidence for the use of EHI to guide decision-making during infliximab (IFX) treatment remains scarce. Therefore, we aimed to characterise the relationships between IFX dose, serum IFX concentrations, EHI, and endoscopic remission (ER). Methods Data were obtained from 118 biologic naïve adult patients with CD enrolled in the phase 4 TAILORIX trial (EudraCT 2011 003038 14). All patients had confirmed active CD at baseline based on clinical, biological, and endoscopic criteria. IFX and EHI (scores ranging from 0–100) were measured using a homogenous mobility shift assay (HMSA) and immunoassay, respectively (Prometheus Laboratories). First, the previously published population pharmacokinetic (popPK) model of the TAILORIX study population was revisited to describe the HMSA data. The effect of EHI, faecal calprotectin (FC), C-reactive protein (CRP), and serum albumin (ALB) on IFX clearance was evaluated. Next, a minimal continuous-time Markov model was developed to describe the time course of EHI within patients. EHI was considered as a three-stage ordinal variable (scores 0–19, 20–49, and 50–100) with the lowest score stage (0–19) indicative of ER. The course-modifying effect of IFX on EHI was assessed. Finally, a generalised linear model was used to describe the relationship between EHI and the probability of attaining ER (Simple Endoscopic Score for CD [SES-CD] ≤2). The predictive ability of EHI for ER was compared with that of FC, CRP, ALB, and IFX using a receiver operating characteristic (ROC) curve analysis. Results The revisited two-compartment popPK model described the IFX data with adequate descriptive and predictive accuracies. EHI, FC, CRP, and ALB at week (w)0 were not found to explain interpatient variability in IFX clearance. In contrast, higher IFX at w14 was associated with a higher probability of achieving EHI <20 at w14 (Figure 1). The probability of attaining EHI <20 at w14 was predicted to increase more than four-fold when IFX at w14 was targeted at 10 mg/L instead of 5 mg/L (Table 1). EHI and FC equally well predicted the probability of attaining ER at the same time point (Figure 2, Table 2). Conclusion EHI, FC, ALB, and CRP at w0 should not be considered for a priori IFX dose optimisation. Nevertheless, a posteriori IFX dose optimisation (based on IFX concentrations measurements) towards a predefined IFX concentration at w14 may lead to lower post-induction EHI scores and thus improved ER rates. An IFX target of 10 mg/L at w14 is associated with four-fold higher normalisation of EHI as compared to the commonly used target of 5 mg/L.