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

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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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Data Availability

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank William Turner, PhD, and Ira Mills, PhD, employees of Parexel, for medical writing assistance, which was funded by Janssen Global Services, LLC. “Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer” has also been published in Clinical Pharmacokinetics as a companion manuscript.

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Authors and Affiliations

  1. Janssen Research & Development, Turnhoutseweg 30, 2340, Beerse, Belgium

    An Van den Bergh, Jan Snoeys, Loeckie De Zwart & Mario Monshouwer

  2. Janssen Research & Development, San Diego, CA, USA

    Peter Ward

  3. Janssen Research & Development, Los Angeles, CA, USA

    Angela Lopez-Gitlitz

  4. Janssen Research & Development, Spring House, PA, USA

    Daniele Ouellet & Caly Chien

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  1. An Van den Bergh
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Contributions

Writing (original draft preparation): AVdB, JS, LDZ, PW, AL-G, DO, MM, and CC. Writing (review and editing): AVdB, JS, LDZ, PW, AL-G, DO, MM, and CC. Research design: AVdB, JS, LDZ, PW, MM, and CC. Performing the research: AVdB and JS. Data analysis: AVdB and JS.

Corresponding author

Correspondence to An Van den Bergh.

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Funding

This study was funded by Janssen Research & Development. Editorial assistance was provided by William Turner, PhD, and Ira Mills, PhD, of Parexel, with funding from Janssen Global Services, LLC.

Conflicts of Interest

An Van den Bergh, Jan Snoeys, Loeckie De Zwart, Peter Ward, Angela Lopez-Gitlitz, Daniele Ouellet, Mario Monshouwer, and Caly Chien are current or former employees of Janssen Research & Development and hold/held stock in Johnson & Johnson.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors.

Informed Consent

As this was a modeling and simulation study that did not include human subjects, informed consent was not required.

Additional information

Daniele Ouellet and Caly Chien were employees of Janssen Research & Development during the conduct of the study, analysis, and interpretation of the results.

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Van den Bergh, A., Snoeys, J., De Zwart, L. et al. Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model. Clin Pharmacokinet 59, 1149–1160 (2020). https://doi.org/10.1007/s40262-020-00881-3

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  • DOI: https://doi.org/10.1007/s40262-020-00881-3

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