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1

Drevin, Guillaume, Marie Briet, Caroline Bazzoli, Emmanuel Gyan, Aline Schmidt, Hervé Dombret, Corentin Orvain, et al. "Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial." Pharmaceutics 14, no. 4 (April 5, 2022): 792. http://dx.doi.org/10.3390/pharmaceutics14040792.

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Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6–8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m2/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375–1167) and 2200 ng/mL·hr (range: 933–4683), respectively. The median metabolic ratio was 0.32 (range: 0.1–0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study.
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2

Zucchetti, Massimo, Amerigo Boiardi, Antonio Silvani, Idria Parisi, Stefano Piccolrovazzi, and Maurizio D'Incalci. "Distribution of daunorubicin and daunorubicinol in human glioma tumors after administration of liposomal daunorubicin." Cancer Chemotherapy and Pharmacology 44, no. 2 (June 17, 1999): 173–76. http://dx.doi.org/10.1007/s002800050964.

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3

&NA;. "Daunorubicin see Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 354 (June 1991): 8. http://dx.doi.org/10.2165/00128415-199103540-00027.

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4

Cusack, B. J., Stephan P. Young, Robert E. Vestal, and Richard D. Olson. "Age-related pharmacokinetics of daunorubicin and daunorubicinol following intravenous bolus daunorubicin administration in the rat." Cancer Chemotherapy and Pharmacology 39, no. 6 (February 28, 1997): 505–12. http://dx.doi.org/10.1007/s002800050606.

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5

Choi, Min-Koo, Im-Sook Song, Dae-Duk Kim, Suk-Jae Chung, and Chang-Koo Shim. "Altered Pharmacokinetics of Daunorubicin in Rats with CCl4-Induced Hepatic Injury." Journal of Pharmacy & Pharmaceutical Sciences 10, no. 4 (September 16, 2007): 443. http://dx.doi.org/10.18433/j3mw28.

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PURPOSE. The effect of CCl4-induced experimental hepatic injury (CCl4-EHI) on the pharmacokinetics of daunorubicin was investigated systemically in rats, in an attempt to elucidate the major determinants of the effect of CCl4-EHI on the pharmacokinetics of the drug. METHODS. CCl4-EHI was induced in rats by a single intraperitoneal injection of CCl4 (1mL/kg rat), and a 24 h fasting period. Daunorubicin was administered intravenously to control and EHI rats at a dose of 11.3 mg/mL/kg and the in vivo pharmacokinetics was studied. The in vitro uptake of the drug into isolated hepatocytes and canalicular liver plasma membrane (cLPM) vesicles, as well as the liver microsomal degradation of the drug, were also determined. RESULTS. The area under the plasma concentration-time curve (AUC) of daunorubicin was increased by 1.6 times, resulting in a 34% decrease in the systemic clearance (CL) in rats with CCl4-EHI. The apparent biliary (CLbile) and urinary (CLurine) clearance of the drug were unchanged, whereas the AUC of daunorubicinol, the major metabolite of daunorubicin, was decreased by 66% in rats with CCl4-EHI. EHI seemed to affect the hepatobiliary elimination of the drug in several ways: the in vitro intrinsic sinusoidal uptake clearance was decreased by 20%; the in vitro intrinsic canalicular excretion clearance of the drug was increased by 1.7 times; and the in vitro liver microsomal degradation of daunorubicin was significantly retarded. CONCLUSIONS. CCl4-EHI appears to impair the hepatic metabolism of daunorubicin, thereby decreasing the CL and increasing the AUC of daunorubicin.
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6

Albrecht, K. W., S. Leenstra, P. J. M. Bakker, J. H. Beijnen, D. Troost, P. Kaaijk, and D. A. Bosch. "High concentration of daunorubicin and daunorubicinol in human malignant astrocytomas after systemic administration of liposomal daunorubicin." Clinical Neurology and Neurosurgery 99 (July 1997): S231. http://dx.doi.org/10.1016/s0303-8467(97)82346-3.

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7

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 1184 (January 2008): 15. http://dx.doi.org/10.2165/00128415-200811840-00044.

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8

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 562 (August 1995): 6. http://dx.doi.org/10.2165/00128415-199505620-00017.

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9

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 392 (March 1992): 5. http://dx.doi.org/10.2165/00128415-199203920-00013.

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10

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 398 (April 1992): 6. http://dx.doi.org/10.2165/00128415-199203980-00014.

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11

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 407 (June 1992): 5. http://dx.doi.org/10.2165/00128415-199204070-00010.

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12

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 898 (April 2002): 6. http://dx.doi.org/10.2165/00128415-200208980-00016.

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13

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 1263 (August 2009): 15. http://dx.doi.org/10.2165/00128415-200912630-00046.

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14

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 1243 (March 2009): 18–19. http://dx.doi.org/10.2165/00128415-200912430-00055.

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15

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 1257 (June 2009): 17–18. http://dx.doi.org/10.2165/00128415-200912570-00053.

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16

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 338 (February 1991): 4. http://dx.doi.org/10.2165/00128415-199103380-00018.

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17

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 357 (June 1991): 6. http://dx.doi.org/10.2165/00128415-199103570-00024.

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18

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 1297 (April 2010): 21. http://dx.doi.org/10.2165/00128415-201012970-00062.

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19

&NA;. "Daunorubicin." Reactions Weekly &NA;, no. 1333 (January 2011): 19. http://dx.doi.org/10.2165/00128415-201113330-00057.

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20

Nikanjam, Mina, Edmund Capparelli, Jeffrey E. Lancet, Jonathan E. Kolitz, Arthur C. Louie, and Gary J. Schiller. "Enhanced Cytarabine and Daunorubicin Population Pharmacokinetics When Administered As CPX-351: A Novel Liposomal Formulation Not Requiring Dose Reduction for Mild Renal or Hepatic Dysfunction." Blood 128, no. 22 (December 2, 2016): 3955. http://dx.doi.org/10.1182/blood.v128.22.3955.3955.

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Abstract Introduction: CPX-351 (Vyxeos) is a novel liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio that has been studied in a phase III clinical trial for secondary acute myeloid leukemia. The current study investigated pharmacokinetic and pharmacodynamic relationships of this liposomal formulation. Methods: CPX-351 pharmacokinetic data from a Phase I study of patients (median age: 62, range 24-81 years) with relapsed and refractory acute myeloid leukemia were used for the analysis. CPX-351 was given as a 90-minute infusion on days 1, 3, and 5 of induction therapy at doses ranging from 3 to 134 Units/m2 (1 unit: 1 mg cytarabine/0.44 mg daunorubicin). Plasma samples were obtained between 45 minutes and 11 days after the start of the day 1 infusion. Cytarabine, daunorubicin, and the concentration of metabolites (uracil arabinoside, daunorubicinol) were determined using liquid chromatography-tandem mass spectrometry. Liposomal membranes were dissolved prior to cytarabine and daunorubicin measurements thus drug concentrations represented combined liposomal and non-liposomal drug. Population pharmacokinetic modeling was completed using nonlinear mixed effects modeling (NONMEM v. VII). The relationship between exposure (AUC) and response data including: 1. achievement of complete remission (logistic regression) and 2. time to recovery of WBC or platelets over the course of initial induction therapy (Cox proportional hazard regression) were explored using statistical software (SAS v. 9.4). Results: 39 patients (3589 samples) were evaluated. Median (range) of laboratory values prior to treatment were: serum creatinine 0.90 (0.6-1.6) mg/dL, total bilirubin 0.60 (0.20 -1.8) mg/dL, AST 28 (12 - 124) U/L, and ALT 27 (15-151) U/L. Liposomal cytarabine and daunorubicin were evaluatedseparately as one compartment models with their respective metabolites (uracil arabinoside, daunorubicinol) added to each model and best fit as a two compartment metabolite model. Weight was an independent predictor of liposomal cytarabine and daunorubicin and metabolite volumes of distribution (Vd), however age, gender, AST, ALT, total bilirubin, and serum creatinine were not independent predictors of clearance (CL) or Vd. The final model demonstrated a liposomal CL of 0.094 and 0.108 L/hr and Vd of 4.6 and 3.5 L for cytarabine and daunorubicin, respectively. Inter-subject variability was 52% and 44% for CL and 117% and 146% for liposomal Vd for cytarabine and daunorubicin. Liposomal cytarabine and daunorubicin had terminal half-lives of 33.9 and 22.0 hr as compared to the published values of 3.0 and 18.5 hr for non-liposomal cytarabine and daunorubicin, respectively. The typical AUCs for the maximum tolerated dose of 101 U/m2 were 1990.6 and 762.1 mcg*hr/mL for cytarabine and daunorubicin respectively, which were a thousand-fold greater than published non-liposomal values. Complete remission after first induction was achieved in 21% of patients (8 out of 39). Despite the large dose and AUC ranges (60.9 - 4901.6 cytarabine, 29.0 - 1572.9 daunorubicin mcg*hr/mL) identified, no significant differences were present between the achievement of complete remission and AUC for cytarabine (p=0.37) or daunorubicin (p=0.26). WBC recovery was achieved at a median of 28 days (n=15; range 21-53 days) while platelet recovery occurred at a median of 35 days (n= 13; range 14-42 days). The remaining patients did not achieve WBC or platelet recovery following initial induction due to residual disease and the majority received a second induction. AUC vs. time to WBC recovery (p=0.077 cytarabine, p=0.0531 daunorubicin) showed a trend toward significance, however no associations were seen with AUC and time to platelet recovery (p=0.60 cytarabine, p=0.81 daunorubicin). Conclusions: The liposomal cytarabine-daunorubicin formulation led to a low clearance and small volume of distribution strongly supporting slow release with prolonged exposure and that no dose modification will be needed in this patient population based on renal or hepatic function. Increased exposure may lead to longer time to WBC recovery, but this will need to be confirmed with larger studies. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals, plc. Disclosures Louie: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Schiller:Incyte Corporation: Research Funding.
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21

Alves, Ana Catarina, Daniela Ribeiro, Miguel Horta, José L. F. C. Lima, Cláudia Nunes, and Salette Reis. "A biophysical approach to daunorubicin interaction with model membranes: relevance for the drug's biological activity." Journal of The Royal Society Interface 14, no. 133 (August 2017): 20170408. http://dx.doi.org/10.1098/rsif.2017.0408.

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Daunorubicin is extensively used in chemotherapy for diverse types of cancer. Over the years, evidence has suggested that the mechanisms by which daunorubicin causes cytotoxic effects are also associated with interactions at the membrane level. The aim of the present work was to study the interplay between daunorubicin and mimetic membrane models composed of different ratios of 1,2-dimyristoyl- sn -glycero- 3 -phosphocholine (DMPC), sphingomyelin (SM) and cholesterol (Chol). Several biophysical parameters were assessed using liposomes as mimetic model membranes. Thereby, the ability of daunorubicin to partition into lipid bilayers, its apparent location within the membrane and its effect on membrane fluidity were investigated. The results showed that daunorubicin has higher affinity for lipid bilayers composed of DMPC, followed by DMPC : SM, DMPC : Chol and lastly by DMPC : SM : Chol. The addition of SM or Chol into DMPC membranes not only increases the complexity of the model membrane but also decreases its fluidity, which, in turn, reduces the amount of anticancer drug that can partition into these mimetic models. Fluorescence quenching studies suggest a broad distribution of the drug across the bilayer thickness, with a preferential location in the phospholipid tails. The gathered data support that daunorubicin permeates all types of membranes to different degrees, interacts with phospholipids through electrostatic and hydrophobic bonds and causes alterations in the biophysical properties of the bilayers, namely in membrane fluidity. In fact, a decrease in membrane fluidity can be observed in the acyl region of the phospholipids. Ultimately, such outcomes can be correlated with daunorubicin's biological action, where membrane structure and lipid composition have an important role. In fact, the results indicate that the intercalation of daunorubicin between the phospholipids can also take place in rigid domains, such as rafts that are known to be involved in different receptor processes, which are important for cellular function.
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22

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1395 (March 2012): 17–18. http://dx.doi.org/10.2165/00128415-201213950-00056.

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23

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1397 (April 2012): 14. http://dx.doi.org/10.2165/00128415-201213970-00046.

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24

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 751 (May 1999): 7. http://dx.doi.org/10.2165/00128415-199907510-00019.

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25

&NA;. "Daunorubicin/mitoxantrone." Reactions Weekly &NA;, no. 1158 (June 2007): 12. http://dx.doi.org/10.2165/00128415-200711580-00029.

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26

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1363 (August 2011): 16. http://dx.doi.org/10.2165/00128415-201113630-00058.

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27

&NA;. "Daunorubicin/pirarubicin." Reactions Weekly &NA;, no. 1366 (August 2011): 13. http://dx.doi.org/10.2165/00128415-201113660-00044.

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28

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1371 (October 2011): 14. http://dx.doi.org/10.2165/00128415-201113710-00049.

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29

&NA;. "Doxorubicin/daunorubicin." Reactions Weekly &NA;, no. 439 (February 1993): 8. http://dx.doi.org/10.2165/00128415-199304390-00040.

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30

&NA;. "Doxorubicin/daunorubicin." Reactions Weekly &NA;, no. 471 (October 1993): 8. http://dx.doi.org/10.2165/00128415-199304710-00036.

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31

&NA;. "Daunorubicin liposomal." Reactions Weekly &NA;, no. 814 (August 2000): 6–7. http://dx.doi.org/10.2165/00128415-200008140-00011.

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32

&NA;. "Daunorubicin liposomal." Reactions Weekly &NA;, no. 829 (November 2000): 7. http://dx.doi.org/10.2165/00128415-200008290-00018.

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33

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1399 (April 2012): 12–13. http://dx.doi.org/10.2165/00128415-201213990-00040.

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34

&NA;. "Daunorubicin/doxorubicin." Reactions Weekly &NA;, no. 373 (October 1991): 5. http://dx.doi.org/10.2165/00128415-199103730-00023.

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35

&NA;. "Daunorubicin/doxorubicin." Reactions Weekly &NA;, no. 423 (October 1992): 7. http://dx.doi.org/10.2165/00128415-199204230-00026.

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36

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1213 (August 2008): 16. http://dx.doi.org/10.2165/00128415-200812130-00046.

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37

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1106 (June 2006): 10. http://dx.doi.org/10.2165/00128415-200611060-00029.

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38

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 898 (April 2002): 6. http://dx.doi.org/10.2165/00128415-200208980-00015.

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39

&NA;. "Cyclophosphamide/daunorubicin." Reactions Weekly &NA;, no. 1258 (June 2009): 13. http://dx.doi.org/10.2165/00128415-200912580-00043.

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&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1280 (November 2009): 18–19. http://dx.doi.org/10.2165/00128415-200912800-00057.

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41

&NA;. "Daunorubicin/doxorubicin." Reactions Weekly &NA;, no. 1252 (May 2009): 19. http://dx.doi.org/10.2165/00128415-200912520-00064.

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42

&NA;. "Daunorubicin/doxorubicin." Reactions Weekly &NA;, no. 292 (March 1990): 5. http://dx.doi.org/10.2165/00128415-199002920-00014.

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43

&NA;. "Daunorubicin/doxorubicin." Reactions Weekly &NA;, no. 348 (April 1991): 7. http://dx.doi.org/10.2165/00128415-199103480-00027.

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44

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 354 (June 1991): 8. http://dx.doi.org/10.2165/00128415-199103540-00026.

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45

&NA;. "Daunorubicin/mitoxantrone." Reactions Weekly &NA;, no. 1309 (July 2010): 18. http://dx.doi.org/10.2165/00128415-201013090-00054.

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46

&NA;. "Daunorubicin/idarubicin." Reactions Weekly &NA;, no. 946 (April 2003): 8–9. http://dx.doi.org/10.2165/00128415-200309460-00024.

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&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1291 (March 2010): 17. http://dx.doi.org/10.2165/00128415-201012910-00050.

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48

&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1294 (March 2010): 16. http://dx.doi.org/10.2165/00128415-201012940-00047.

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49

&NA;. "Daunorubicin/tretinoin." Reactions Weekly &NA;, no. 1301 (May 2010): 18. http://dx.doi.org/10.2165/00128415-201013010-00064.

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&NA;. "Cytarabine/daunorubicin." Reactions Weekly &NA;, no. 1059 (July 2005): 10. http://dx.doi.org/10.2165/00128415-200510590-00025.

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