Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin
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The purpose of the study was to construct a population pharmacokinetic model for pegylated liposomal doxorubicin and use the final model to investigate the discrimination performance of pharmacokinetic metrics (e.g., Cmax, AUC and partial AUC) of various analytes (e.g., liposome encapsulated doxorubicin, free doxorubicin and total doxorubicin) for the identification of formulation differences by means of Monte Carlo simulations.
A model was simultaneously built to characterize the concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin using NONMEM. The different scenarios associated with changes in release rate (Rel) were simulated based on the final parameters. 500 simulated virtual bioequivalence (BE) studies were performed for each scenario, and power curves for the probability of declaring BE were also computed.
The concentration time profiles of liposome-encapsulated doxorubicin and free doxorubicin were well described by a one- and two-compartment model, respectively. pAUC0-24 h and pAUC0-48 h of free doxorubicin was most responsive to changes in the Rel when the Rel (test)/Rel (reference) ratios decreased. In contrast, when the Rel (test) increased, AUC0-t of liposome-encapsulated doxorubicin was the most responsive metric.
In addition to the traditional metrics, partial AUC should be included for the BE assessment of pegylated liposomal doxorubicin.
Key wordsbioequivalence modeling and simulation partial AUC pegylated liposomal doxorubicin population pharmacokinetics
Analysis of variance
Area under the curve
Area under the curve up to last measurable time point
Clearance of the free doxorubicin
Uptake clearance of liposome-encapsulated doxorubicin by the reticuloendothelial system
Conditional weighted residuals
European medicines agency
First-order conditional estimation
International clinical trials registry platform
Individual weighted residuals
Liter per hour
Milligram per square meter
Nanogram per milliliter
Nonlinear mixed effects modeling
Partial area under the curve
Inter-compartmental clearance of the free doxorubicin
Release rate of the free doxorubicin from the liposome carrier
Root mean square error
Taiwan food and drug administration
Time to maximum concentration
United states food and drug administration
Volume of distribution of the liposome-encapsulated doxorubicin
Central volume of distribution of the free doxorubicin
Peripheral volume of distribution of the free doxorubicin
Wings for nonlinear mixed effects modeling
The views expressed in this article are the author’s personal opinions and do not necessarily reflect the recommendations of the Taiwan CDE.
- 3.Drugs@FDA Website Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm Accessed 2 September 2017.
- 4.Taiwan Food and Drug Administration Website Available at: http://www.fda.gov.tw/MLMS/H0001.aspx Accessed 2 September 2017.
- 6.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Draft Guidance for Industry: Doxorubicin HCl. Revised April 2017. Available from: https://www.fda.gov/downloads/Drugs/.../Guidances/UCM199635.pdf Accessed 2 September 2017.
- 7.European Medicines Agency. Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product. Final February 2013. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500140351.pdf. Accessed 2 September 2017.
- 11.Macheras P, Iliadis A. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics: homogeneous and heterogeneous approaches. In: Karalis V, editor. Modeling and simulation in bioequivalence. 2rd ed. Switzerland: Springer; 2016. p. 227–54.Google Scholar
- 12.Sm A, S S. Bioequivalence Study of Pegylated Doxorubicin Hydrochloride Liposome (PEGADRIA) and DOXIL® in Ovarian Cancer Patients: Physicochemical Characterization and Pre-clinical Studies. J Nanosci Nanotechnol 2016;07(02). https://doi.org/10.4172/2157-7439.1000361.
- 14.Zhang X, Duan J, Kesisoglou F, Novakovic J, Amidon GL, Jamei M, et al. Mechanistic oral absorption modeling and simulation for formulation development and bioequivalence evaluation: report of an FDA public workshop. CPT Pharmacometrics Syst Pharmacol. 2017;6(8):492–5. https://doi.org/10.1002/psp4.12204.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Kontny NE, Wurthwein G, Joachim B, Boddy AV, Krischke M, Fuhr U, et al. Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years. Cancer Chemother Pharmacol. 2013;71(3):749–63. https://doi.org/10.1007/s00280-013-2069-1.CrossRefPubMedGoogle Scholar
- 25.Nageeb El-Helaly S, Abd Elbary A, Kassem MA, El-Nabarawi MA. Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation, characterization, ex vivo, bio-distribution and in vivo pharmacokinetic studies. Drug Deliv. 2017;24(1):692–700. https://doi.org/10.1080/10717544.2017.1309476.CrossRefPubMedGoogle Scholar
- 27.Lee LH, Choi C, Gershkovich P, Barr AM, Honer WG, Procyshyn RM. Proposing the use of partial AUC as an adjunctive measure in establishing bioequivalence between deltoid and gluteal Administration of Long-Acting Injectable Antipsychotics. Eur J Drug Metab Pharmacokinet. 2016;41(6):659–64. https://doi.org/10.1007/s13318-016-0348-z.CrossRefPubMedGoogle Scholar
- 28.Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000;89(5):1037–47. https://doi.org/10.1002/1097-0142(20000901)89:5<1037::AID-CNCR13>3.0.CO;2-Z.CrossRefPubMedGoogle Scholar