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27.04.2020 | Original Research Article | Ausgabe 9/2020

Clinical Pharmacokinetics 9/2020

Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer

Clinical Pharmacokinetics > Ausgabe 9/2020
Ignacio Duran, Joan Carles, Iurie Bulat, Peter Hellemans, Anna Mitselos, Peter Ward, James Jiao, Danielle Armas, Caly Chien
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s40262-020-00882-2) contains supplementary material, which is available to authorized users.
Study PCR1012 was presented in part at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting, 8–12 March, 2016, San Diego, CA, USA.
Please see the companion article titled “Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model.”


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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