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Erschienen in: Clinical Pharmacokinetics 9/2020

27.04.2020 | Original Research Article

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

verfasst von: Ignacio Duran, Joan Carles, Iurie Bulat, Peter Hellemans, Anna Mitselos, Peter Ward, James Jiao, Danielle Armas, Caly Chien

Erschienen in: Clinical Pharmacokinetics | Ausgabe 9/2020

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Abstract

Background and Objectives

Two phase I studies assessed the drug–drug interaction potential of apalutamide as a substrate and perpetrator.

Methods

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.

Results

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.

Conclusions

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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Metadaten
Titel
Pharmacokinetic Drug–Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer
verfasst von
Ignacio Duran
Joan Carles
Iurie Bulat
Peter Hellemans
Anna Mitselos
Peter Ward
James Jiao
Danielle Armas
Caly Chien
Publikationsdatum
27.04.2020
Verlag
Springer International Publishing
Erschienen in
Clinical Pharmacokinetics / Ausgabe 9/2020
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-020-00882-2

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