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

Research Paper
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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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 

Abbreviations

ANOVA

Analysis of variance

AUC

Area under the curve

AUC0-t

Area under the curve up to last measurable time point

BE

Bioequivalence

CLfree

Clearance of the free doxorubicin

CLres

Uptake clearance of liposome-encapsulated doxorubicin by the reticuloendothelial system

Cmax

Maximum concentration

CWRES

Conditional weighted residuals

E%

Encapsulation percentage

EMA

European medicines agency

FOCE

First-order conditional estimation

ICTRP

International clinical trials registry platform

IIV

Inter-individual variability

IV

Intravenous

IWRES

Individual weighted residuals

k0

Infusion rate

l/h

Liter per hour

m2

Square meter

mg/m2

Milligram per square meter

ng/ml

Nanogram per milliliter

NONMEM

Nonlinear mixed effects modeling

pAUC

Partial area under the curve

Q

Inter-compartmental clearance of the free doxorubicin

Rel

Release rate of the free doxorubicin from the liposome carrier

RES

Reticuloendothelial system

RMSE

Root mean square error

TFDA

Taiwan food and drug administration

Tmax

Time to maximum concentration

USFDA

United states food and drug administration

V1

Volume of distribution of the liposome-encapsulated doxorubicin

V2

Central volume of distribution of the free doxorubicin

V3

Peripheral volume of distribution of the free doxorubicin

WfN

Wings for nonlinear mixed effects modeling

Notes

Disclaimer

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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Copyright information

© 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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