Ignacio Duran1, Joan Carles2, Iurie Bulat3, Peter Hellemans4, Anna Mitselos5, Peter Ward6, James Jiao7, Danielle Armas8, Caly Chien9. 1. Hospital Universitario Virgen del Rocío, Seville, Spain. 2. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 3. ARENSIA Exploratory Medicine, Institute of Oncology Unit, Chisinau, Moldova. 4. Janssen Research & Development, Beerse, Belgium. phellema@its.jnj.com. 5. Janssen Research & Development, Beerse, Belgium. 6. Janssen Research & Development, San Diego, CA, USA. 7. Janssen Research & Development, Raritan, NJ, USA. 8. Celerion, Tempe, AZ, USA. 9. Janssen Research & Development, Spring House, PA, USA.
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 tosingle-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 receivedprobes 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.
RCT Entities:
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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