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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 9/2020

01-09-2020 | Itraconazole | Original Research Article

Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model

Authors: An Van den Bergh, Jan Snoeys, Loeckie De Zwart, Peter Ward, Angela Lopez-Gitlitz, Daniele Ouellet, Mario Monshouwer, Caly Chien

Published in: Clinical Pharmacokinetics | Issue 9/2020

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Abstract

Background

Apalutamide is predominantly metabolized via cytochrome P450 (CYP) 2C8 and CYP3A4, whose contributions change due to autoinduction with repeated dosing.

Objectives

We aimed to predict CYP3A4 and CYP2C8 inhibitor/inducer effects on the steady-state pharmacokinetics of apalutamide and total potency-adjusted pharmacologically active moieties, and simulated drug–drug interaction (DDI) between single-dose and repeated-dose apalutamide coadministered with known inhibitors/inducers.

Methods

We applied physiologically based pharmacokinetic modeling for our predictions, and simulated DDI between single-dose and repeated-dose apalutamide 240 mg coadministered with ketoconazole, gemfibrozil, or rifampicin.

Results

The estimated contribution of CYP2C8 and CYP3A4 to apalutamide metabolism is 58% and 13%, respectively, after single dosing, and 40% and 37%, respectively, at steady-state. Apalutamide exposure is predicted to increase with ketoconazole (maximum observed concentration at steady-state [Cmax,ss] 38%, area under the plasma concentration–time curve at steady-state [AUCss] 51% [pharmacologically active moieties, Cmax,ss 23%, AUCss 28%]) and gemfibrozil (Cmax,ss 32%, AUCss 44% [pharmacologically active moieties, Cmax,ss 19%, AUCss 23%]). Rifampicin exposure is predicted to decrease apalutamide (Cmax,ss 25%, AUCss 34% [pharmacologically active moieties, Cmax,ss 15%, AUCss 19%]).

Conclusions

Based on our simulations, no major changes in the pharmacokinetics of apalutamide or pharmacologically active moieties are expected with strong CYP3A4/CYP2C8 inhibitors/inducers. This observation supports the existing recommendations that no dose adjustments are needed during coadministration of apalutamide and the known inhibitors or inducers of CYP2C8 or CYP3A4.
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Metadata
Title
Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model
Authors
An Van den Bergh
Jan Snoeys
Loeckie De Zwart
Peter Ward
Angela Lopez-Gitlitz
Daniele Ouellet
Mario Monshouwer
Caly Chien
Publication date
01-09-2020
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 9/2020
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-020-00881-3

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