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1
Iorio, Alfonso. "Using pharmacokinetics to individualize hemophilia therapy." Hematology 2017, no. 1 (December 8, 2017): 595–604. http://dx.doi.org/10.1182/asheducation-2017.1.595.
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Abstract Prevention and treatment of bleeding in hemophilia requires that plasma clotting factor activity of the replaced factor exceeds a defined target level. Most clinical decisions in hemophilia are based on implicit or explicit application of pharmacokinetic measures. The large interindividual variability in pharmacokinetics of factor concentrates suggests that relying on the average pharmacokinetic characteristics of factor concentrates would not allow optimizing the treatment of individual patients; for example, adjusting the frequency of infusions and targeting a specific clotting factor activity level on a case-by-case basis. However, individual pharmacokinetic profiles are seldom assessed as part of routine clinical care. Population pharmacokinetics provide options for precise and convenient characterization of pharmacokinetics characteristics of factor concentrates, simplified individual pharmacokinetic profiling, and individualized dosing. Population pharmacokinetics allow for the incorporation of determinants of interpatient variability and reduces the need for extensive postinfusion plasma sampling. Barriers to the implementation of population pharmacokinetics are the need for concentrate-specific pharmacokinetic models, Bayesian calculation power, and specific expertise for production, validation, and appraisal of forecasted estimates. Population pharmacokinetics provide an important theoretical and practical contribution to tailoring the treatment of hemophilia. The need remains for prospective exploration of the clinical impact of tailoring hemophilia treatment based on individual pharmacokinetics, and for the systematic validation of existing software solutions and concentrate-specific models.
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Kamp, Jasper, Erik Olofsen, Thomas K. Henthorn, Monique van Velzen, Marieke Niesters, and Albert Dahan. "Ketamine Pharmacokinetics." Anesthesiology 133, no. 6 (September 30, 2020): 1192–213. http://dx.doi.org/10.1097/aln.0000000000003577.
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Background Several models describing the pharmacokinetics of ketamine are published with differences in model structure and complexity. A systematic review of the literature was performed, as well as a meta-analysis of pharmacokinetic data and construction of a pharmacokinetic model from raw data sets to qualitatively and quantitatively evaluate existing ketamine pharmacokinetic models and construct a general ketamine pharmacokinetic model. Methods Extracted pharmacokinetic parameters from the literature (volume of distribution and clearance) were standardized to allow comparison among studies. A meta-analysis was performed on studies that performed a mixed-effect analysis to calculate weighted mean parameter values and a meta-regression analysis to determine the influence of covariates on parameter values. A pharmacokinetic population model derived from a subset of raw data sets was constructed and compared with the meta-analytical analysis. Results The meta-analysis was performed on 18 studies (11 conducted in healthy adults, 3 in adult patients, and 5 in pediatric patients). Weighted mean volume of distribution was 252 l/70 kg (95% CI, 200 to 304 l/70 kg). Weighted mean clearance was 79 l/h (at 70 kg; 95% CI, 69 to 90 l/h at 70 kg). No effect of covariates was observed; simulations showed that models based on venous sampling showed substantially higher context-sensitive half-times than those based on arterial sampling. The pharmacokinetic model created from 14 raw data sets consisted of one central arterial compartment with two peripheral compartments linked to two venous delay compartments. Simulations showed that the output of the raw data pharmacokinetic analysis and the meta-analysis were comparable. Conclusions A meta-analytical analysis of ketamine pharmacokinetics was successfully completed despite large heterogeneity in study characteristics. Differences in output of the meta-analytical approach and a combined analysis of 14 raw data sets were small, indicative that the meta-analytical approach gives a clinically applicable approximation of ketamine population parameter estimates and may be used when no raw data sets are available. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
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Jeong, Seung-Hyun, Ji-Hun Jang, and Yong-Bok Lee. "Pharmacokinetic Comparison between Methotrexate-Loaded Nanoparticles and Nanoemulsions as Hard- and Soft-Type Nanoformulations: A Population Pharmacokinetic Modeling Approach." Pharmaceutics 13, no. 7 (July 9, 2021): 1050. http://dx.doi.org/10.3390/pharmaceutics13071050.
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The purpose of this study was to identify and explore the differences in pharmacokinetics between different nanoformulations. This was done by comparing the pharmacokinetics of methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid); size of 163.70 ± 10.25 nm] and nanoemulsions (olive oil and Labrasol; size of 173.77 ± 5.76 nm), which represent hard- and soft-type nanoformulations, respectively. In addition, the population pharmacokinetic modeling approach as a useful tool for the comparison of pharmacokinetics between nanoformulations was newly proposed through this study. Significant pharmacokinetic differences were identified between nanoformulations through the new population pharmacokinetic modeling approach. As a result, the formulation type was explored as a significant covariate. The clearance and bioavailability of methotrexate-loaded nanoemulsions tended to decrease by 99% and increase by 19%, respectively, compared to those of the nanoparticles. The exploration of significant pharmacokinetic differences between drug formulations and their correlations presented in this study provide new perspectives on the development of nanoformulations.
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Grzegorzewski, Jan, Janosch Brandhorst, Kathleen Green, Dimitra Eleftheriadou, Yannick Duport, Florian Barthorscht, Adrian Köller, Danny Yu Jia Ke, Sara De Angelis, and Matthias König. "PK-DB: pharmacokinetics database for individualized and stratified computational modeling." Nucleic Acids Research 49, no. D1 (November 5, 2020): D1358—D1364. http://dx.doi.org/10.1093/nar/gkaa990.
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Abstract A multitude of pharmacokinetics studies have been published. However, due to the lack of an open database, pharmacokinetics data, as well as the corresponding meta-information, have been difficult to access. We present PK-DB (https://pk-db.com), an open database for pharmacokinetics information from clinical trials. PK-DB provides curated information on (i) characteristics of studied patient cohorts and subjects (e.g. age, bodyweight, smoking status, genetic variants); (ii) applied interventions (e.g. dosing, substance, route of application); (iii) pharmacokinetic parameters (e.g. clearance, half-life, area under the curve) and (iv) measured pharmacokinetic time-courses. Key features are the representation of experimental errors, the normalization of measurement units, annotation of information to biological ontologies, calculation of pharmacokinetic parameters from concentration-time profiles, a workflow for collaborative data curation, strong validation rules on the data, computational access via a REST API as well as human access via a web interface. PK-DB enables meta-analysis based on data from multiple studies and data integration with computational models. A special focus lies on meta-data relevant for individualized and stratified computational modeling with methods like physiologically based pharmacokinetic (PBPK), pharmacokinetic/pharmacodynamic (PK/PD), or population pharmacokinetic (pop PK) modeling.
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Albitar, Orwa, Sabariah Noor Harun, Hadzliana Zainal, Baharudin Ibrahim, and Siti Maisharah Sheikh Ghadzi. "Population Pharmacokinetics of Clozapine: A Systematic Review." BioMed Research International 2020 (January 8, 2020): 1–10. http://dx.doi.org/10.1155/2020/9872936.
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Background and Objective. Clozapine is a second-generation antipsychotic drug that is considered the most effective treatment for refractory schizophrenia. Several clozapine population pharmacokinetic models have been introduced in the last decades. Thus, a systematic review was performed (i) to compare published pharmacokinetics models and (ii) to summarize and explore identified covariates influencing the clozapine pharmacokinetics models. Methods. A search of publications for population pharmacokinetic analyses of clozapine either in healthy volunteers or patients from inception to April 2019 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded. Results. Twelve studies were included in this review. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. Significant interindividual variations of clozapine pharmacokinetic parameters were found in most of the included studies. Age, sex, smoking status, and cytochrome P450 1A2 were found to be the most common identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models. Conclusions. Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.
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Tang, Bo-Hao, Yue-E. Wu, Chen Kou, Yu-Jie Qi, Hui Qi, Hai-Yan Xu, Stephanie Leroux, et al. "Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants." Antimicrobial Agents and Chemotherapy 63, no. 2 (December 3, 2018): e02336-18. http://dx.doi.org/10.1128/aac.02336-18.
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ABSTRACT Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.
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Egan, Talmage D., Bernou Huizinga, Samir K. Gupta, Rudy L. Jaarsma, Richard J. Sperry, James B. Yee, and Keith T. Muir. "Remifentanil Pharmacokinetics in Obese versus Lean Patients." Anesthesiology 89, no. 3 (September 1, 1998): 562–73. http://dx.doi.org/10.1097/00000542-199809000-00004.
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Background Remifentanil is a short-acting opioid whose pharmacokinetics have been characterized in detail. However, the impact of obesity on remifentanil pharmacokinetics has not been specifically examined. The goal of this study was to investigate the influence of body weight on remifentanil pharmacokinetics. Methods Twelve obese and 12 matched lean subjects undergoing elective surgery received a 1-min remifentanil infusion after induction of anesthesia. Arterial blood samples were collected for determination of remifentanil blood concentrations. Each subject's pharmacokinetic parameters were estimated by fitting a two-compartment model to the concentration versus time curves. Nonlinear mixed-effects population models examining the influence of lean body mass (LBM) and total body weight (TBW) were also constructed. Clinical simulations using the final population model were performed. Results The obese patient cohort reached substantially higher remifentanil concentrations. The individual pharmacokinetic parameters of a two-compartment model were not significantly different between the obese versus lean cohorts (unless normalized to TBW). The final population model scaled central clearance and the central and peripheral distribution volumes to LBM. The simulations illustrated that remifentanil pharmacokinetics are not grossly different in obese versus lean subjects and that TBW based dosing in obese patients can result in excessively high remifentanil concentrations. Conclusions The essential findings of the study are that remifentanil's pharmacokinetics are not appreciably different in obese versus lean subjects and that remifentanil pharmacokinetic parameters are therefore more closely related to LBM than to TBW. Clinically this means that remifentanil dosing regimens should be based on ideal body weight (or LBM) and not TBW.
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Stepensky, David. "Pharmacokinetics of Toxin-Derived Peptide Drugs." Toxins 10, no. 11 (November 20, 2018): 483. http://dx.doi.org/10.3390/toxins10110483.
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Toxins and venoms produced by different organisms contain peptides that have evolved to have highly selective and potent pharmacological effects on specific targets for protection and predation. Several toxin-derived peptides have become drugs and are used for the management of diabetes, hypertension, chronic pain, and other medical conditions. Despite the similarity in their composition (amino acids as the building blocks), toxin-derived peptide drugs have very profound differences in their structure and conformation, in their physicochemical properties (that affect solubility, stability, etc.), and subsequently in their pharmacokinetics (the processes of absorption, distribution, metabolism, and elimination following their administration to patients). This review summarizes and critically analyzes the pharmacokinetic properties of toxin-derived peptide drugs: (1) the relationship between the chemical structure, physicochemical properties, and the pharmacokinetics of the specific drugs, (2) the major pharmacokinetic properties and parameters of these drugs, and (3) the major pharmacokinetic variability factors of the individual drugs. The structural properties of toxin-derived peptides affect their pharmacokinetics and pose some limitations on their clinical use. These properties should be taken into account during the development of new toxin-derived peptide drugs, and for the efficient and safe use of the clinically approved drugs from this group in the individual patients.
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Li, Qiao, Yan Yang, Ting Zhou, Rui Wang, Na Li, Min Zheng, Yuan-Yuan Li, et al. "A Compositive Strategy to Study the Pharmacokinetics of TCMs: Taking Coptidis Rhizoma, and Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma as Examples." Molecules 23, no. 8 (August 15, 2018): 2042. http://dx.doi.org/10.3390/molecules23082042.
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Pharmacokinetic studies are crucial for elucidating the effective constituents and formula compatibility of traditional Chinese medicines (TCMs). However, studies have usually been limited to single dosages and detection of systemic blood concentrations. To obtain comprehensive pharmacokinetic information, here we propose a multi-dosage and multi-sampling (blood from portal vein or systemic circulation, and liver) strategy to comparatively study the pharmacokinetics of multi-form TCMs, i.e., pure constituents, TCMs, or TCM formula extracts. Based on this strategy, we studied the pharmacokinetics of pure berberine, berberine in Coptidis Rhizoma (CRE), and berberine in Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma extracts (CR-GRE). After simple calculation and comparison of the obtained area under the curve (AUC) values, the results revealed the drastically different pharmacokinetic properties of pure berberine compared to CRE and CR-GRE. The results contribute to explaining the pharmacological loss of berberine activity after purification and the compatibility of the CR-GR drug pair. The results also innovatively showed that it was intestinal absorption that differentiated the pharmacokinetics of CRE and pure berberine, and CRE and CR-GRE. In conclusion, we propose a composite strategy to comparatively study the pharmacokinetics of TCMs, which could provide sufficient information to obtain a comprehensive view, before follow-up mechanism-of-action studies.
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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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Jacobson, J. M., M. Davidian, P. M. Rainey, R. Hafner, R. H. Raasch, and B. J. Luft. "Pyrimethamine pharmacokinetics in human immunodeficiency virus-positive patients seropositive for Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 40, no. 6 (June 1996): 1360–65. http://dx.doi.org/10.1128/aac.40.6.1360.
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Pyrimethamine pharmacokinetics were studied in 11 human immunodeficiency virus (HIV)-positive patients who were seropositive for exposure to Toxoplasma gondii and were taking zidovudine (AIDS Clinical Trials Group Protocol 102). Pyrimethamine was administered at 50 mg daily for 3 weeks to achieve steady state, and pharmacokinetic profiles were determined after administration of the last dose. Noncompartmental and compartmental analyses were performed. Population pharmacokinetic analysis assuming a one-compartment model yielded the following estimates: area under the 24-h concentration-time curve, 42.7 +/- 12.3 micrograms.h/ml; halflife, 139 +/- 34 h; clearance, 1.28 +/- 0.41 liters/h; volume of distribution, 246 +/- 641; and absorption rate constant, 1.5 +/- 1.3 liters/h. These values are similar to those seen in subjects without HIV infection. Pyrimethamine pharmacokinetics did not differ significantly in those subjects who were intravenous drug users. Adverse effects were noted in 73% of those initially enrolled in this study, leading to discontinuation for 38%. No association was noted between pyrimethamine levels and the incidence of adverse events. No significant differences were seen in zidovudine pharmacokinetic parameters obtained from studies performed before and during treatment with pyrimethamine. In summary, pyrimethamine exhibited pharmacokinetics in HIV-infected patients that were similar to those in non-HIV-infected subjects and it did not alter the pharmacokinetics of zidovudine in these patients.
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Urbánek, Karel. "Pharmacological characteristics of subcutaneously administered monoclonal antibodies." Gastroenterologie a hepatologie 77, no. 6 (December 30, 2023): 539–43. http://dx.doi.org/10.48095/ccgh2023539.
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Summary: Subcutaneous administration is a simple method of parenteral administration with a minimum of possible complications, also suitable for home treatment. Moreover, it can be used to influence the pharmacokinetics of the administered drug. For therapeutically used monoclonal antibodies, it brings several advantages in terms of simplifying treatment and improving patient’s adherence. In addition, it appears that by targeting pharmacokinetic parameters, lower immunogenicity, and achievement of pharmacokinetic-pharmacodynamic targets can be achieved and thus, likely improve treatment outcomes. Key words: monoclonal antibodies – pharmacokinetics – pharmacodynamics – subcutaneous administration
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Warren, Katherine E., Cynthia M. McCully, Thomas J. Walsh, and Frank M. Balis. "Effect of Fluconazole on the Pharmacokinetics of Doxorubicin in Nonhuman Primates." Antimicrobial Agents and Chemotherapy 44, no. 4 (April 1, 2000): 1100–1101. http://dx.doi.org/10.1128/aac.44.4.1100-1101.2000.
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ABSTRACT Antifungal prophylaxis in cancer patients who are undergoing chemotherapy is associated with prolonged neutropenia. We measured the effect of fluconazole on doxorubicin pharmacokinetics in nonhuman primates to determine if neutropenia is related to a pharmacokinetic interaction that delays the clearance of the chemotherapeutic agent. Fluconazole pretreatment had no effect on doxorubicin pharmacokinetics.
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Cook, Aaron M. "Pharmacokinetic Alterations of Antimicrobials in the Critically Ill." Journal of Pharmacy Practice 18, no. 2 (April 2005): 75–83. http://dx.doi.org/10.1177/0897190004273568.
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Critical illness is accompanied by multiple physiologic alterations that affect the pharmacokinetics of antimicrobials. Although the pharmacokinetics of a number of antimicrobials have been studied in critically ill individuals, an understanding of the physiological alterations in critical illness and general pharmacokinetic principles of antimicrobials is imperative for appropriate selection, dosing, and prediction of toxicity.
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Hao, Guo-Xiang, Sophie Teng, Evelyne Jacqz-Aigrain, and Wei Zhao. "DO WE HAVE A CONSENSUS TO APPLY MODEL-BASED AMINOGLYCOSIDE THERAPY: A REVIEW OF POPULATION PHARMACOKINETIC MODELS." Archives of Disease in Childhood 101, no. 1 (December 14, 2015): e1.51-e1. http://dx.doi.org/10.1136/archdischild-2015-310148.55.
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Background and ObjectiveAminoglycosides remain the standard antibiotic therapy for Gram-negative infections in both adults and children. The pharmacokinetic modeling approach has been widely used to evaluate aminoglycosides therapy. The aim of the present study is to review the published population pharmacokinetic models of commonly used aminoglycosides (gentamycin, amikacin and tobramycin), in order to determine if there was a consensus to apply model-based personalized aminoglycoside therapy in routine clinical practice.MethodsThe bibliographic search was performed electronically using PubMed on 30th January 2015, following the search strategy: “((population Pharmacokinetics) OR (Pharmacokinetic modeling)) AND (gentamycin OR gentamicin OR amikacin OR tobramycin)”.ResultsA total of 49 articles were identified. Persistent variabilities exist in terms of structure model; typical pharmacokinetic parameters and identified covariates.ConclusionA pharmacokinetic meta-analysis is required to evaluate the study-related factors influencing the pharmacokinetics of aminoglycosides. A clinical evaluation of pharmacokinetic model of aminoglycosides is required to demonstrate its clinical utility.
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Muralidharan, Gopal, Richard J. Fruncillo, Marlynne Micalizzi, Donald G. Raible, and Steven M. Troy. "Effects of Age and Sex on Single-Dose Pharmacokinetics of Tigecycline in Healthy Subjects." Antimicrobial Agents and Chemotherapy 49, no. 4 (April 2005): 1656–59. http://dx.doi.org/10.1128/aac.49.4.1656-1659.2005.
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ABSTRACT The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.
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Fish, Douglas N., and Edward Abraham. "Pharmacokinetics of a Clarithromycin Suspension Administered via Nasogastric Tube to Seriously Ill Patients." Antimicrobial Agents and Chemotherapy 43, no. 5 (May 1, 1999): 1277–80. http://dx.doi.org/10.1128/aac.43.5.1277.
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ABSTRACT The pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite were studied on two separate occasions after nasogastric administration of 500 mg of a clarithromycin suspension to 16 seriously ill adults in an intensive care unit. The clarithromycin suspension appeared to be adequately absorbed, and the pharmacokinetics of neither clarithromycin nor 14-(R)-hydroxyclarithromycin differed significantly between the two dosing periods. No substantial differences in pharmacokinetics were observed compared to previously published studies of other adult populations. Minimal intrapatient variability of pharmacokinetic parameters was observed in these seriously ill patients.
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Pandit, Rahul, Mirjam A. F. M. Gerrits, and Eugène J. F. M. Custers. "Assessing Knowledge of Pharmacokinetics in an Integrated Medical Curriculum." Medical Science Educator 31, no. 6 (October 18, 2021): 1967–73. http://dx.doi.org/10.1007/s40670-021-01442-4.
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AbstractPharmacokinetics is the branch of pharmacology that describes how the body processes drugs. As most physicians will prescribe drugs during their career, knowledge of pharmacokinetics is indispensable for medical students. Students, however, experience pharmacokinetics as difficult, probably due to its abstract and mathematical nature. In many medical curricula, pharmacokinetic topics are taught and examined as a part of integrated medical courses. As pharmacokinetics is a relatively small subject, unit examinations contain only few questions on the topic. The combination of a difficult subject and a few questions has raised concerns that students could perform poorly in pharmacokinetics and still pass the examinations and, hence, end up with insufficient knowledge of pharmacokinetics. In this study, we investigate this issue by contrasting students’ performance on pharmacokinetics questions with their performance on the rest of the examinations (all non-pharmacokinetics questions lumped together). The results expressed as pass-fail scores showed that students failed more often on the pharmacokinetics part of the test than on the other questions, in two consecutive academic years. Despite the suboptimal knowledge in pharmacokinetics, students can still acquire their bachelor’s degree. These results show that poor knowledge in pharmacokinetics could be a side effect of curricular integration. Attention should therefore be paid to provide insight into one’s own performance in individual disciplines. This would avoid knowledge deficiency and incompetence in the future.
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Shikov, Alexander N., Elena V. Flisyuk, Ekaterina D. Obluchinskaya, and Olga N. Pozharitskaya. "Pharmacokinetics of Marine-Derived Drugs." Marine Drugs 18, no. 11 (November 9, 2020): 557. http://dx.doi.org/10.3390/md18110557.
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Marine organisms represent an excellent source of innovative compounds that have the potential for the development of new drugs. The pharmacokinetics of marine drugs has attracted increasing interest in recent decades due to its effective and potential contribution to the selection of rational dosage recommendations and the optimal use of the therapeutic arsenal. In general, pharmacokinetics studies how drugs change after administration via the processes of absorption, distribution, metabolism, and excretion (ADME). This review provides a summary of the pharmacokinetics studies of marine-derived active compounds, with a particular focus on their ADME. The pharmacokinetics of compounds derived from algae, crustaceans, sea cucumber, fungus, sea urchins, sponges, mollusks, tunicate, and bryozoan is discussed, and the pharmacokinetics data in human experiments are analyzed. In-depth characterization using pharmacokinetics is useful for obtaining information for understanding the molecular basis of pharmacological activity, for correct doses and treatment schemes selection, and for more effective drug application. Thus, an increase in pharmacokinetic research on marine-derived compounds is expected in the near future.
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Dolton, Michael J., Roger J. M. Brüggemann, David M. Burger, and Andrew J. McLachlan. "Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis." Antimicrobial Agents and Chemotherapy 58, no. 11 (September 8, 2014): 6879–85. http://dx.doi.org/10.1128/aac.03777-14.
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ABSTRACTPosaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.
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Kalam, Muhammad Nasir, Muhammad Fawad Rasool, Asim Ur Rehman, and Naveed Ahmed. "Clinical Pharmacokinetics of Propranolol Hydrochloride: A Review." Current Drug Metabolism 21, no. 2 (June 11, 2020): 89–105. http://dx.doi.org/10.2174/1389200221666200414094644.
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Background: Nobel laureate Sir James Black’s molecule, propranolol, still has broad potential in cardiovascular diseases, infantile haemangiomas and anxiety. A comprehensive and systematic review of the literature for the summarization of pharmacokinetic parameters would be effective to explore the new safe uses of propranolol in different scenarios, without exposing humans and using virtual-human modeling approaches. Objective: This review encompasses physicochemical properties, pharmacokinetics and drug-drug interaction data of propranolol collected from various studies. Methods: Clinical pharmacokinetic studies on propranolol were screened using Medline and Google Scholar databases. Eighty-three clinical trials, in which pharmacokinetic profiles and plasma time concentration were available after oral or IV administration, were included in the review. Results: The study depicts that propranolol is well absorbed after oral administration. It has dose-dependent bioavailability, and a 2-fold increase in dose results in a 2.5-fold increase in the area under the curve, a 1.3-fold increase in the time to reach maximum plasma concentration and finally, 2.2 and 1.8-fold increase in maximum plasma concentration in both immediate and long-acting formulations, respectively. Propranolol is a substrate of CYP2D6, CYP1A2 and CYP2C19, retaining potential pharmacokinetic interactions with co-administered drugs. Age, gender, race and ethnicity do not alter its pharmacokinetics. However, in renal and hepatic impairment, it needs a dose adjustment. Conclusion: Physiochemical and pooled pharmacokinetic parameters of propranolol are beneficial to establish physiologically based pharmacokinetic modeling among the diseased population.
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Mallick, Pankajini. "Utilizing in vitro transporter data in IVIVE-PBPK: an overview." ADMET and DMPK 5, no. 4 (December 23, 2017): 201–11. http://dx.doi.org/10.5599/admet.5.4.441.
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In vitro-in vivo extrapolation (IVIVE) integrated in physiologically-based pharmacokinetic (PBPK) models have been increasingly used during drug discovery and development processes to predict human pharmacokinetic (PK) parameters. Drug transporters can influence drug pharmacokinetics and are key aspects contributing to the development of a successful drug. This review provides a snapshot of challenges or shortcomings of in vitro and in vivo techniques for understanding the contribution of drug transporters to a drug’s pharmacokinetics. The paper also describes the potential of IVIVE-PBPK models as prospective approaches to predict the role of drug transporters in drug discovery and development.
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García-Quintanilla, Laura, Andrea Luaces-Rodríguez, María Gil-Martínez, Cristina Mondelo-García, Olalla Maroñas, Víctor Mangas-Sanjuan, Miguel González-Barcia, et al. "Pharmacokinetics of Intravitreal Anti-VEGF Drugs in Age-Related Macular Degeneration." Pharmaceutics 11, no. 8 (July 31, 2019): 365. http://dx.doi.org/10.3390/pharmaceutics11080365.
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Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance.
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Zhao, W., and TINN-Global Study Group. "P113 Population pharmacokinetics and dosing optimization of azlocillin in neonates." Archives of Disease in Childhood 104, no. 6 (May 17, 2019): e64.3-e65. http://dx.doi.org/10.1136/archdischild-2019-esdppp.151.
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BackgroundAzlocillin is prescribed for the treatment of infections in neonatal clinical practice, however, the optimized dose is still questionable due to the lack of pharmacokinetic study Thus, we aim to evaluate the population pharmacokinetics of azlocillin and optimize dosing regimen in order to improve azlocillin treatment in neonates.MethodsThis is a prospective, open label pharmacokinetic study of azlocillin. Blood samples were collected using an opportunistic sampling design. Theplasma concentrations ofazlocillinwere determined by high performance liquid chromatography method with UV detection. Population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM software.ResultsNinety-five neonates (postmenstrual age (PMA) range 32.1–42.0 weeks) were included in this study. A total of 167 azlocillin concentrations were available for the final analysis. A one-compartment model with first-order elimination best fitted the data. Covariate analysis demonstrated that current weight, birth weight and postnatal age had significant effect on azlocillin pharmacokinetics. MonteCarlo simulation demonstrated that for the common pathogens with MIC of 8 mg/liter, the currently used dosage regimen (100 mg/kg, q12h) resulted in 61.2% of newborns achieved the pharmacodynamic target (drug concentrations above MIC during 70% of the dosing interval) with a potential risk of underdosing. When shortening the dosing interval to 8 hours, the target could be achieved in 89.3% of patients, using the MIC break point of 8 mg/liter.ConclusionThe population pharmacokinetics characteristics of azlocillin were assessed in neonates. An optimal dosage regimen of azlocillin was established based on developmental pharmacokinetics-pharmacodynamics in this vulnerable population.Disclosure(s)Nothing to disclose.
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Amsden, Jarrett R., Paul O. Gubbins, Scott McConnell, and Elias Anaissie. "Steady-State Pharmacokinetics of Oral Voriconazole and Its Primary Metabolite,N-Oxide Voriconazole, Pre- and Post-Autologous Peripheral Stem Cell Transplantation." Antimicrobial Agents and Chemotherapy 57, no. 7 (April 29, 2013): 3420–23. http://dx.doi.org/10.1128/aac.00046-13.
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ABSTRACTVoriconazole (VCZ) is frequently utilized for prevention and treatment of invasive fungal infections in peripheral stem cell transplant (PSCT) patients. We performed an open-label pharmacokinetic study to compare VCZ andN-oxide voriconazole (N-oxide VCZ) pharmacokinetics in patients pre- and post-PSCT. Ten patients completed both sampling periods. The pharmacokinetics of VCZ were unchanged; however, those ofN-oxide VCZ were significantly different pre- and post-PSCT.
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Debnath, Subhashis, and T. H. Harish Kumar. "An Overview on Pharmacokinetics and Pharmacokinetic Modeling." Asian Journal of Research in Pharmaceutical Science 10, no. 2 (2020): 124. http://dx.doi.org/10.5958/2231-5659.2020.00023.5.
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MacFadyen, Robert J., Peter A. Meredith, and Henry L. Elliott. "Enalapril Clinical Pharmacokinetics and Pharmacokinetic-Pharmacodynamic Relationships." Clinical Pharmacokinetics 25, no. 4 (October 1993): 274–82. http://dx.doi.org/10.2165/00003088-199325040-00003.
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Schoenwald, R. D. "Modelling of ocular pharmacokinetic processes: Corneal pharmacokinetics." Experimental Eye Research 55 (September 1992): 228. http://dx.doi.org/10.1016/0014-4835(92)91010-u.
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Mertens, Martijn J., Erik Olofsen, Anton G. L. Burm, James G. Bovill, and Jaap Vuyk. "Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics." Anesthesiology 100, no. 4 (April 1, 2004): 795–805. http://dx.doi.org/10.1097/00000542-200404000-00008.
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Background The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. Methods The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. Results A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. Conclusions Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.
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Ginsberg, Brian, Scott Howell, Peter S. A. Glass, Judith O. Margolis, Allison K. Ross, Guy de L. Dear, and Steven L. Shafer. "Pharmacokinetic Model-driven Infusion of Fentanyl in Children." Anesthesiology 85, no. 6 (December 1, 1996): 1268–75. http://dx.doi.org/10.1097/00000542-199612000-00007.
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Background This study determined the accuracy of previously defined adult fentanyl pharmacokinetics in children having surgery; from this population, the pharmacokinetics of fentanyl were characterized in children when administered via a computerized assisted continuous-infusion device. Methods Twenty children between the ages of 2.7 and 11 y scheduled to undergo elective noncardiac surgery were studied. After induction, anesthesia was maintained with 60% nitrous oxide in oxygen supplemented with fentanyl (n = 10) or fentanyl plus isoflurane (n = 10). Fentanyl was administered via computerized assisted continuous-infusion to target concentrations determined by clinical requirements. Plasma fentanyl concentrations were measured and used to evaluate the performance of the fentanyl pharmacokinetics and then to determine a new set of pharmacokinetic parameters and the variance in the context-sensitive half-times simulated for these patients. Results The original adult fentanyl pharmacokinetics resulted in a positive bias (10.4%), indicating that measured concentrations were mostly greater than predicted. A two-compartment model with age and weight as covariates provided the optimal pharmacokinetic parameters. These resulted in a residual performance error of -1.1% and a median absolute performance error of 17.4%. The context-sensitive times determined from this pediatric population were considerably shorter than the context-sensitive times previously published for adults. Conclusions The pharmacokinetics of fentanyl administered by computerized assisted continuous-infusion differ between adults and children. The newly derived parameters are probably more suitable to determine infusion schemes of up to 4 h in children between the ages of 2 and 11 y.
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Bailey, James M. "Technique for Quantifying the Duration of Intravenous Anesthetic Effect." Anesthesiology 83, no. 5 (November 1, 1995): 1095–103. http://dx.doi.org/10.1097/00000542-199511000-00024.
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Abstract Background Several recent studies have analyzed the relationship between pharmacokinetic parameters and the rate of decrease in concentration after discontinuation of a continuous drug infusion. Although these studies have clarified our understanding of those aspects of pharmacokinetics most relevant to anesthesia practice, they do not directly address the issue of the duration of drug effect, which will be a function of both pharmacokinetic and pharmacodynamic variables. This paper extends these concepts by presenting a method to unify pharmacokinetics and pharmacodynamics in a measure of duration of drug effect that is applicable when the drug effect is assessed in a binary, response/no response fashion.
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Child, Robert B., and Mark J. Tallon. "Cannabidiol (CBD) Dosing: Plasma Pharmacokinetics and Effects on Accumulation in Skeletal Muscle, Liver and Adipose Tissue." Nutrients 14, no. 10 (May 18, 2022): 2101. http://dx.doi.org/10.3390/nu14102101.
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Oral cannabidiol (CBD) consumption is widespread in North America and Europe, as it has analgesic, neuroprotective and antitumor effects. Although oral CBD consumption in humans affords beneficial effects in epileptic and inflammatory states, its pharmacokinetics and subsequent uptake into tissue are largely unknown. This study investigated plasma pharmacokinetics and accumulation of CBD in gastrocnemius muscle, liver and adipose tissue in adult rats following oral gavage. CBD was fed relative to body mass at 0 (control), 30, 115, or 230 mg/Kg/day for 28 days; with 6 males and 6 females per dosing group. Pharmacokinetics were assessed on day 1 and day 28 in the group receiving CBD at 115 mg/Kg/day. The rise in tissue CBD was closely related to specific pharmacokinetic parameters, and adipose tissue levels were ~10 to ~100 fold greater than liver or muscle. Tissue CBD levels were moderately correlated between adipose and muscle, and adipose and liver, but were highly correlated for liver and muscle. CBD feeding resulted in several gender-specific effects, including changes in pharmacokinetics, relationships between pharmacokinetic parameters and tissue CBD and differences in tissue CBD levels. CBD accumulation in mammalian tissues has the potential to influence receptor binding and metabolism; therefore, the present findings may have relevance for developing oral dosing regimens.
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Li, Hua. "Volumetric absorptive microsampling in pharmacokinetic studies." International Journal of Pharmacokinetics 4, no. 2 (December 2019): IPK04. http://dx.doi.org/10.4155/ipk-2020-0001.
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Biography: Hua Li is currently a Bioanalytical Research Scientist in the NBE Pharmacokinetics Group in the Biotherapeutics Discovery Department at Boehringer Ingelheim (CT, USA). She earned her MA in molecular, cellular and developmental biology from the University of Kansas (KS, USA). While pursuing her master’s degree, she worked as a research assistant on Caenorhabditis elegans genetics. After graduation, she started my career as a research associate and laboratory manager at the Stem Cell Center of Yale University (CT, USA). Her main roles included investigating the essential proteins that play a critical role in the division and differentiation of mouse testes stem cells, as well as administrative responsibilities for a laboratory of around 12 people including graduate students, post-docs and laboratory technician. Since 2008, her career has been focusing on the quantitation of pharmacokinetics and pharmacodynamics study of protein therapeutics. Over the past 12 years, she has witnessed a tremendous expansion of new technologies, devices and theories in the pharmacokinetics/pharmacodynamics field, all of which have helped us better serve the patient community all over the world. Hua Li speaks to the International Journal of Pharmacokinetics about the use of volumetric absorptive microsampling in pharmacokinetic studies and their methodology on the application of Mitra® microsampling for pharmacokinetic bioanalysis of monoclonal antibodies in rats.
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Song, Shuliang, Qiang Wei, Ke Wang, Qiong Yang, Yu Wang, Aiguo Ji, and Guanjun Chen. "Fluorescent Labeling of Polymannuronic Acid and Its Distribution in Mice by Tail Vein Injection." Marine Drugs 20, no. 5 (April 25, 2022): 289. http://dx.doi.org/10.3390/md20050289.
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Polymannuronic acid (PM) possesses more pharmacological activities than sodium alginate, but there have been few studies on its absorption mechanism, tissue distribution, and pharmacokinetics. Studies of pharmacokinetics and tissue distribution are necessary to elucidate the pharmacological effects of PM. Thus, we used fluorescein isothiocyanate (FITC) to produce fluorescently labeled PM (FITC-PM) and detected the distribution and pharmacokinetics of PM in vivo via tail vein injection. The results demonstrate that the FITC-PM showed high stability in different pH solutions. After the tail vein injection, FITC-PM tended to be distributed in the kidney, followed by the liver and in the heart, spleen, and lungs at lower concentrations. Pharmacokinetic analysis showed that the elimination rate constant of FITC-PM was 0.24, the half-life time was 2.85 h, the peak concentration was 235.17 μg/mL, the area under the curve was 631.48 μg/mL·h, the area under the curve by statistical moment was 1843.15 μg/mL·h2, the mean residence time was 2.92 h, and the clearance rate was 79.18 mL/h. These results indicate that FITC-PM could be used for PM distribution and pharmacokinetic studies, and the studies of pharmacokinetics and tissue distribution provided basic information that can be used to further clarify PM pharmacodynamic mechanisms.
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Song, Shuliang, Qiang Wei, Ke Wang, Qiong Yang, Yu Wang, Aiguo Ji, and Guanjun Chen. "Fluorescent Labeling of Polymannuronic Acid and Its Distribution in Mice by Tail Vein Injection." Marine Drugs 20, no. 5 (April 25, 2022): 289. http://dx.doi.org/10.3390/md20050289.
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Polymannuronic acid (PM) possesses more pharmacological activities than sodium alginate, but there have been few studies on its absorption mechanism, tissue distribution, and pharmacokinetics. Studies of pharmacokinetics and tissue distribution are necessary to elucidate the pharmacological effects of PM. Thus, we used fluorescein isothiocyanate (FITC) to produce fluorescently labeled PM (FITC-PM) and detected the distribution and pharmacokinetics of PM in vivo via tail vein injection. The results demonstrate that the FITC-PM showed high stability in different pH solutions. After the tail vein injection, FITC-PM tended to be distributed in the kidney, followed by the liver and in the heart, spleen, and lungs at lower concentrations. Pharmacokinetic analysis showed that the elimination rate constant of FITC-PM was 0.24, the half-life time was 2.85 h, the peak concentration was 235.17 μg/mL, the area under the curve was 631.48 μg/mL·h, the area under the curve by statistical moment was 1843.15 μg/mL·h2, the mean residence time was 2.92 h, and the clearance rate was 79.18 mL/h. These results indicate that FITC-PM could be used for PM distribution and pharmacokinetic studies, and the studies of pharmacokinetics and tissue distribution provided basic information that can be used to further clarify PM pharmacodynamic mechanisms.
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Song, Shuliang, Qiang Wei, Ke Wang, Qiong Yang, Yu Wang, Aiguo Ji, and Guanjun Chen. "Fluorescent Labeling of Polymannuronic Acid and Its Distribution in Mice by Tail Vein Injection." Marine Drugs 20, no. 5 (April 25, 2022): 289. http://dx.doi.org/10.3390/md20050289.
Full textAbstract:
Polymannuronic acid (PM) possesses more pharmacological activities than sodium alginate, but there have been few studies on its absorption mechanism, tissue distribution, and pharmacokinetics. Studies of pharmacokinetics and tissue distribution are necessary to elucidate the pharmacological effects of PM. Thus, we used fluorescein isothiocyanate (FITC) to produce fluorescently labeled PM (FITC-PM) and detected the distribution and pharmacokinetics of PM in vivo via tail vein injection. The results demonstrate that the FITC-PM showed high stability in different pH solutions. After the tail vein injection, FITC-PM tended to be distributed in the kidney, followed by the liver and in the heart, spleen, and lungs at lower concentrations. Pharmacokinetic analysis showed that the elimination rate constant of FITC-PM was 0.24, the half-life time was 2.85 h, the peak concentration was 235.17 μg/mL, the area under the curve was 631.48 μg/mL·h, the area under the curve by statistical moment was 1843.15 μg/mL·h2, the mean residence time was 2.92 h, and the clearance rate was 79.18 mL/h. These results indicate that FITC-PM could be used for PM distribution and pharmacokinetic studies, and the studies of pharmacokinetics and tissue distribution provided basic information that can be used to further clarify PM pharmacodynamic mechanisms.
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Cattaneo, Dario, Sara Baldelli, Matteo Cerea, Simona Landonio, Paola Meraviglia, Emanuela Simioni, Valeria Cozzi, et al. "Comparison of theIn VivoPharmacokinetics andIn VitroDissolution of Raltegravir in HIV Patients Receiving the Drug by Swallowing or by Chewing." Antimicrobial Agents and Chemotherapy 56, no. 12 (September 10, 2012): 6132–36. http://dx.doi.org/10.1128/aac.00942-12.
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ABSTRACTThe pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interpatient/intrapatient variability. We investigated the potential contribution of the drug pharmaceutical formulation to RAL pharmacokinetics. We first comparedin vivothe pharmacokinetics of RAL for 67 patients to whom the drug was administered by swallowing the intact tablet with those obtained from 13 HIV-infected patients who chewed the RAL tablet due to swallowing difficulties. Subsequently, we evaluatedin vitrothe dissolution of RAL tablets under different conditions. In thein vivostudy, we found that patients given RAL by chewing the tablets presented pharmacokinetic profiles characterized by significantly higher RAL absorption than did patients receiving the drug by swallowing. Thein vitrostudies showed that when the whole tablets were exposed to an acidic medium, the release of RAL was very low, whereas when the tablets were crushed, the profiles presented significantly higher concentrations of RAL. Crushed tablets tested in water or in a pH 6.8 buffer exhibited prompt and complete dissolution of RAL. HIV-infected patients receiving RAL by chewing the tablet showed higher drug absorption and reduced pharmacokinetic variability compared with patients swallowing the intact tablet. This is related to problems in tablet disintegration and to erratic drug absorption. The amelioration of the RAL pharmaceutical formulation could improve drug pharmacokinetics.
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Hope, William W. "Population Pharmacokinetics of Voriconazole in Adults." Antimicrobial Agents and Chemotherapy 56, no. 1 (November 7, 2011): 526–31. http://dx.doi.org/10.1128/aac.00702-11.
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ABSTRACTVoriconazole is a first-line agent for the treatment of invasive fungal infections. The pharmacology of voriconazole is characterized by extensive interindividual variability and nonlinear pharmacokinetics. The population pharmacokinetics of voriconazole in 64 adults is described. The patient population consisted of 21 healthy volunteers, who received a range of intravenous (i.v.) and oral voriconazole regimens, and 43 patients with proven or probable invasive aspergillosis, who received the currently licensed dosage. Voriconazole concentrations were measured using high-performance liquid chromatography (HPLC). The pharmacokinetic data were modeled using a nonparametric methodology and with a nonlinear pharmacokinetic structural model. The extent and consequences of pharmacokinetic variability were explored using Monte Carlo simulation. The relationship between drug exposure and clinical response was explored using logistic regression. Optimal sampling times were identified using D-optimal design. The fit of the nonlinear model was acceptable. Data from the healthy volunteers provided robust estimates forKmand the maximum rate of enzyme activity (Vmax). The Bayesian parameter estimates were more variable and statistically different in patients than in volunteers. There was a linear relationship between the trough concentration and area under the concentration-time curve (AUC0-12). There was no relationship between the AUC0-12and clinical response. The original parameter values were readily recapitulated using Monte Carlo simulation. Initial i.v. dosing resulted in higher AUC0-12and trough concentrations compared with oral dosing. Sample collection times of 1, 2, 3, 4, 8, and 12 h after an i.v. infusion are maximally informative times for future pharmacokinetic studies.
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Agema, Bram C., Astrid W. Oosten, Sebastiaan D. T. Sassen, Wim J. R. Rietdijk, Carin C. D. van der Rijt, Birgit C. P. Koch, Ron H. J. Mathijssen, and Stijn L. W. Koolen. "Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain." Cancers 13, no. 11 (June 2, 2021): 2768. http://dx.doi.org/10.3390/cancers13112768.
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Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.
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Mileva, R., and A. Milanova. "Doxycycline pharmacokinetics in mammalian species of veterinary interest – an overview." BULGARIAN JOURNAL OF VETERINARY MEDICINE 25, no. 1 (2022): 1–20. http://dx.doi.org/10.15547/bjvm.2321.
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Doxycycline is a broad-spectrum tetracycline antibiotic widely used in veterinary medicine. The current review aims to summarise the available data about pharmacokinetics in mammalian species of veterinary interest and to indicate the basic strategies for refining dosage regimens in order to use this antibiotic reasonably. Additionally, the available data about population pharmacokinetics are reviewed as this approach exhibits a number of benefits in terms of determination of drug pharmacokinetics, prediction of drug disposition and interpretation of the variations in the pharmacokinetic parameters. Further research with animal species of veterinary interest and pathogens causing diseases in animals is needed to clarify the pharmacokinetics and pharmacodynamics of doxycycline.
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Schneiderman, J. H. "Topiramate: Pharmacokinetics and Pharmacodynamics." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 25, S3 (August 1998): S3—S5. http://dx.doi.org/10.1017/s031716710003482x.
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ABSTRACT:Topiramate is a structurally novel anti-epileptic drug with at least 3 postulated mechanisms of action including: 1) potentiation of GABA responses, 2) impairment of AMPA/kainate glutamate receptors and 3) suppression of high frequency action potential firing. It has a favourable pharmacokinetic profile with rapid absorption, good bio-availability, linear pharmacokinetics, relatively long half-life and limited pharmacokinetic drug interactions. However, topiramate can reduce the estrogen component of oral contraceptive medications. Women may require birth control preparations containing 50 (Xg of estrogen. Topiramate clearance is reduced in severe renal failure and increased by enzyme-inducing antiepileptic drugs. The dose of topiramate may have to be reduced in renal failure or when withdrawing enzyme inducers.
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Naseem, Urooj, Fatima Iqbal, and Gul Shahnaz. "A Comprehensive Insight on Pharmacokinetics." Global Drug Design & Development Review I, no. I (December 30, 2016): 27–37. http://dx.doi.org/10.31703/gdddr.2016(i-i).04.
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Pharmacokinetics can be defined as what the body does to a drug. The basic parameters of pharmacokinetics are discussed here including absorption, distribution, metabolism, and excretion. Characteristics and pathways taken by these drugs are determined by these parameters. The mechanism followed by these parameters are also discussed. Furthermore, the factors affecting these parameters including physicochemical factors, physical factors and pharmaceutical factors are also explored. Different routes of drug absorption and main barriers to drug distribution are also explained. The pharmacokinetic values namely acid dissociation constant, bioavailability and solubility are briefly explained. There is a detailed insight into the pathways of metabolism (Phase I and II reactions) and excretion.
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Borsuk-De Moor, Agnieszka, and Paweł Wiczling. "The use of population modeling to optimize dosing of drugs used in anaesthesiology and intensive care." Postępy Polskiej Medycyny i Farmacji 8 (June 9, 2021): 18–23. http://dx.doi.org/10.5604/01.3001.0014.9188.
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Effective pharmacotherapy requires an adequate drug dose that maximizes the effectiveness of therapy while minimizing adverse effects. Difficulties in dose selection arise from interindividual differences in drug pharmacokinetics and pharmacodynamics. Population modeling describes pharmacokinetic and pharmacodynamic processes in a population, taking into account the relationships in each patient, differences between patients, and the influence of covariates on drug pharmacokinetics and pharmacodynamics. The aim of this study was to develop population models for drugs used in anesthesiology and intensive care in special patient populations. The pharmacokinetics of sufentanil was described in infants and children after epidural and intravenous administration. The estimated absorption rate constant from the epidural space suggests slow systemic absorption of sufentanil and the possibility of flip-flop kinetics, which results in a slower decline in plasma concentrations at the end of drug administration compared with intravenous administration. The dependence of metabolic clearance on body weight and age was also demonstrated. A population model for the pharmacokinetics of tigecycline was developed for patients with sepsis or septic shock. No relationship between pharmacokinetic parameters and patient characteristics was detected, and the estimated interindividual and inter-occasion variability for clearance was small. This suggests that a universal dose is sufficient to achieve homogeneous drug exposure in critically ill patients. The pharmacokinetics of caspofungin was described in critically ill patients. The clearance and volume of central compartment showed systematic increase over time that was not explained by the covariates. The estimated increase in clearance values for three consecutive doses results in a clinically relevant reduction in drug exposure. The developed population models extend the knowledge of the pharmacokinetics of sufentanyl, tigecycline, and caspofungin. Simulations based on these models can aid the dosing decision-making process.
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Wang, Xiaoxing, Wenwen Du, Xianglin Zhang, and Pengmei Li. "The Influence of Different Disease States on Rituximab Pharmacokinetics." Current Drug Metabolism 21, no. 12 (December 30, 2020): 938–46. http://dx.doi.org/10.2174/1389200221666200719004035.
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Background: The anti-CD20 antibody rituximab, which promotes the selective depletion of CD20 positive B cells, was the first targeted therapy that was approved for the treatment of B-cell malignancies, and it is now widely prescribed in both malignant and non-malignant, immune-related diseases. However, the cause of its various clinical responses in certain diseases, have not been clearly elucidated. The variabilities in inter-individual pharmacokinetic and the emerging evidence of the relationships between pharmacokinetic and pharmacodynamic may provide a better understanding of this drug. Methods: We searched and summarized the latest published articles on rituximab pharmacokinetic profiles and the pharmacokinetic/pharmacodynamic models in different patient populations, including B-cell malignancies, rheumatoid arthritis, ANCA-associated vasculitis, and glomerular kidney diseases. Results: Most pharmacokinetic data are drawn from clinical studies in oncology clinical practice. Body weight, gender, and antigen-related factors are proven to be the key factors affecting rituximab pharmacokinetics. In addition, the positive exposure-response relations were reported, which provide encouraging evidence for individualized therapies. While in immune disorders, especially in the off-labeled indications, pharmacokinetic studies are quite limited. Compared with that in B-cell malignancies, the differences in the pharmacokinetic parameters may be attributed to the different pathogeneses of diseases, mechanisms of action and dosing strategies. However, the correlation between drug exposure and clinical outcomes remains unclear. Conclusion: Here, we provide an overview of the complexities associated with rituximab pharmacokinetics and pharmacodynamics in different diseases. Although many influencing factors need to be verified in future studies, a better understanding of the relationships between pharmacokinetic and pharmacodynamic may assist in optimizing rituximab clinical practice.
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Vincze, István, Rita Czermann, Zsuzsanna Nagy, Mária Kovács, Michael Neely, Róbert Farkas, Ibolya Kocsis, Gellért Balázs Karvaly, and Csaba Kopitkó. "Assessment of Antibiotic Pharmacokinetics, Molecular Biomarkers and Clinical Status in Critically Ill Adults Diagnosed with Community-Acquired Pneumonia and Receiving Intravenous Piperacillin/Tazobactam and Hydrocortisone over the First Five Days of Intensive Care: An Observational Study (STROBE Compliant)." Journal of Clinical Medicine 11, no. 14 (July 16, 2022): 4140. http://dx.doi.org/10.3390/jcm11144140.
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Severe community-acquired pneumonia (CAP) is a condition that frequently requires intensive care and, eventually, can cause to death. Piperacillin/tazobactam antibiotic therapy is employed as an empiric intravenous regimen, in many cases supplemented with intravenous bolus hydrocortisone treatment. The individual and condition-dependent pharmacokinetic properties of these drugs may lead to therapeutic failure. The impact of systemic inflammation, as well as of hydrocortisone on the altered pharmacokinetics of piperacillin is largely unknown. The protocol of a clinical study aimed at the characterization of the pharmacokinetics of piperacillin and tazobactam and its association with the concentrations of inflammatory markers and adrenal steroids during CAP therapy will be investigated in up to 40 critically ill patients. The serum concentrations of piperacillin and tazobactam, cortisol, cortisone, corticosterone and 11-deoxycortisol and interleukin-6 levels, as well as routine clinical chemistry and hematology parameters will be monitored from the beginning of treatment for up to five days. Nonparametric population pharmacokinetic modeling and Monte-Carlo simulations will be performed to make estimates of the pharmacokinetics of piperacillin and tazobactam and the probability of pharmacokinetic-pharmacodynamic target attainment. The observed individual characteristics and changes will be correlated with clinical and laboratory findings. The protocol of the observational study will be designed following the STROBE guideline.
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Matsuo, Yumiko, Toru Ishibashi, Alan S. Hollister, and Toshihiro Wajima. "Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients." Antimicrobial Agents and Chemotherapy 59, no. 11 (August 17, 2015): 6755–62. http://dx.doi.org/10.1128/aac.00799-15.
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ABSTRACTPeramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.
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Aquino, Maria, Maria Tinoco, Joana Bicker, Amílcar Falcão, Marília Rocha, and Ana Fortuna. "Therapeutic Drug Monitoring of Amikacin in Neutropenic Oncology Patients." Antibiotics 12, no. 2 (February 11, 2023): 373. http://dx.doi.org/10.3390/antibiotics12020373.
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Amikacin is the antibiotic of choice for the treatment of Gram-negative infections, namely, those in neutropenic oncology patients. No populational pharmacokinetic studies are currently available reporting amikacin pharmacokinetics in neutropenic oncology patients despite their specific pathophysiological features and treatments. A large-scale retrospective study was herein conducted to specifically investigate the effects that tumor diseases have on the pharmacokinetic parameters of amikacin and identify whether chemotherapy, the lag time between administration of chemotherapy and amikacin, age and renal function contribute to amikacin pharmacokinetics in neutropenic cancer patients. A total of 1180 pharmacokinetic analysis from 629 neutropenic patients were enrolled. The daily dose administered to oncology patients was higher than that administered to non-oncology patients (p < 0.0001). No statistical differences were found in amikacin concentrations, probably because drug clearance was increased in cancer patients (p < 0.0001). Chemotherapy influenced amikacin pharmacokinetics and drug clearance decreased as the lag time enhanced. The elderly group revealed no statistical differences between the doses administered to both the oncology groups, suggesting that the impact of ageing is stronger than chemotherapy. Our research suggests that cancer patients require higher initial doses of amikacin, as well as when chemotherapy is received less than 30 days before amikacin treatment has started.
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Wang, Xiaohu, Jin Tang, Chaozhuang Shen, Xingwen Wang, Hua Hu, and Haitang Xie. "Research Progress of Population Pharmacokinetic of Metformin." BioMed Research International 2022 (December 19, 2022): 1–10. http://dx.doi.org/10.1155/2022/4071111.
Full textAbstract:
Metformin is commonly used as first-line treatment for T2DM (type2 diabetes mellitus). Owing to the high pharmacokinetic (PK) variability, several population pharmacokinetic (PPK) models have been developed for metformin to explore potential covariates that affect its pharmacokinetic variation. This comprehensive review summarized the published PPK studies of metformin, aimed to summarize PPK models of metformin. Most studies described metformin pharmacokinetics as a 2-compartment (2-CMT) model with 4 study describing its pharmacokinetics as 1-compartment (1-CMT). Studies on metformin PPK have shown that obesity, creatinine clearance (CLCr), gene polymorphism, degree of renal function damage, and pathological conditions all have a certain impact on the PK parameters of metformin. It is particularly important to formulate individualized dosing regimens. For future PPK studies of metformin, we believe that more attention should be paid to special populations.
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Knebel, William, John C. Davis, William D. Sanders, Barri Fessler, Cheryl Yarboro, Frank Pucino, and Dimitrios T. Boumpas. "The Pharmacokinetics and Pharmacodynamics of Fludarabine in Rheumatoid Arthritis." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 18, no. 6 (November 12, 1998): 1224–29. http://dx.doi.org/10.1002/j.1875-9114.1998.tb03141.x.
Full textAbstract:
Study Objective. To describe the pharmacokinetics and pharmacodynamics of fludarabine in patients with rheumatoid arthritis (RA).Design. Open‐label, staggered trial conducted in conjunction with a phase I‐II clinical trial.Setting. Government research hospital.Patients. Twenty‐six patients with refractory RA.Intervention. Fludarabine 20 or 30 mg/m2/day was administered as a 0.5‐hour infusion for 3 consecutive days (1 cycle) for 6 months (1 cycle/mo).Measurements and Main Results. Serial plasma samples were collected for pharmacokinetic analysis on day 2 of the first cycle of therapy. Relationships between pharmacokinetic parameters and hematologic and efficacy parameters were examined. The disposition of fludarabine was characterized by a two‐compartment model. There were no differences in pharmacokinetics between the low‐ and high‐dose groups. The mean ± SD total clearance, volume of distribution at steady state, and β‐half‐life were 13.68 ± 5.1 L/hour, 170.08 ± 86.5 L, and 10.9 ± 3.1 hours, respectively. The volume of the peripheral compartment was approximately twice as large as the volume of the central compartment, indicating a significant amount of tissue distribution. No significant pharmacodynamic relationships were observed between pharmacokinetic parameters and hematologic and efficacy parameters.Conclusion. Fludarabine pharmacokinetics in patients with RA are characterized by an intermediate‐length distribution phase (∼ 40 min), terminal half‐life of 10.9 hours, and significant amount of tissue distribution.
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Kim, Tae, Subindra Thapa, Da Lee, Seung Chung, Jun Lim, Hyeon Jeong, Chang Song, et al. "Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats." Pharmaceutics 10, no. 3 (September 6, 2018): 152. http://dx.doi.org/10.3390/pharmaceutics10030152.
Full textAbstract:
This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by a novel liquid chromatography-tandem mass spectrometry method. Gastrointestinal damage was determined by measuring ulcer area and ulcer lesion index of the stomach. Oral administration of aceclofenac induced significant gastric ulceration, which was inhibited by esomeprazole administration. Following concurrent administration of aceclofenac and esomeprazole, overall pharmacokinetic profiles of aceclofenac and metabolic conversion to diclofenac were unaffected by esomeprazole. Aceclofenac metabolism and pharmacokinetics were not subject to significant food effects, whereas bioavailability of esomeprazole decreased in fed compared to fasting conditions. In contrast, the pharmacokinetics of aceclofenac and esomeprazole were significantly altered by different dosing vehicles. These results suggest that co-administration of esomeprazole with aceclofenac may reduce aceclofenac-induced gastrointestinal complications without significant pharmacokinetic interactions. The optimal combination and clinical significance of the benefits of the combination of aceclofenac and esomeprazole need to be further evaluated.