Background and Objectives
Two phase I studies assessed the drug–drug interaction potential of apalutamide as a substrate and perpetrator.
Study A randomized 45 healthy men to single-dose apalutamide 240 mg alone or with strong inhibitors of cytochrome P450 (CYP)3A4 (itraconazole) or CYP2C8 (gemfibrozil). In study B, 23 patients with castration-resistant prostate cancer received probes for CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2C8 (pioglitazone), and transporter substrates for P-glycoprotein (P-gp) (fexofenadine) and breast cancer resistance protein (BCRP)/organic anion transporting polypeptide (OATP) 1B1 (rosuvastatin) at baseline and after repeat once-daily administration of apalutamide 240 mg to steady state.
Systemic exposure (area under the plasma concentration–time curve) to single-dose apalutamide increased 68% with gemfibrozil but was relatively unchanged with itraconazole (study A). Apalutamide reduced systemic exposure to midazolam ↓92%, omeprazole ↓85%, S-warfarin ↓46%, fexofenadine ↓30%, rosuvastatin ↓41%, and pioglitazone ↓18% (study B). After a single dose, apalutamide is predominantly metabolized by CYP2C8, and less by CYP3A4.
Co-administration of apalutamide with CYP3A4, CYP2C19, CYP2C9, P-gp, BCRP or OATP1B1 substrates may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended.
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The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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The authors thank William Turner, PhD, and Ira Mills, PhD, employees of Parexel, for medical writing assistance, which was funded by Janssen Global Services, LLC.
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.
Conflict of interest
Ignacio Duran reports personal fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pharmacyclics, Roche Genentech, and Sanofi, non-financial support from AstraZeneca, Ipsen, and Roche Genentech, and grants from AstraZeneca and Roche Genentech outside the submitted work. Joan Carles reports advisory roles for Astellas, Bayer, Bristol-Myers Squibb, Johnson & Johnson, MSD Oncology, Pfizer, Roche, and Sanofi, and speakers’ bureau roles for Asofarma, Astellas, Bayer, and Johnson & Johnson outside the submitted work. Iurie Bulat has no conflicts of interest that are directly relevant to the content of this article. Danielle Armas reports support from Janssen to her employer, Celerion, during the conduct of the study. Peter Hellemans, Anna Mitselos, Peter Ward, James Jiao, and Caly Chien are current or former employees of Janssen Research & Development and hold/held stock in Johnson & Johnson.
Protocols of both studies were reviewed by an independent ethics committee and institutional review board, and both studies were conducted in accordance with Good Clinical Practice and applicable regulatory requirements.
Consent to participate
Participants in both studies provided written informed consent.
Please see the companion article titled “Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model.”
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Duran, I., Carles, J., Bulat, I. et al. Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer. Clin Pharmacokinet 59, 1135–1148 (2020). https://doi.org/10.1007/s40262-020-00882-2