Investigation of the Discriminatory Ability of Pharmacokinetic Metrics for the Bioequivalence Assessment of PEGylated Liposomal Doxorubicin

  • Li-feng HsuEmail author
Research Paper



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 words

bioequivalence 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


Maximum concentration


Conditional weighted residuals


Encapsulation percentage


European medicines agency


First-order conditional estimation


International clinical trials registry platform


Inter-individual variability




Individual weighted residuals


Infusion rate


Liter per hour


Square meter


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


Reticuloendothelial system


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.


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pharmaceutical Science, Center for Drug Evaluation (CDE)TaipeiTaiwan

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