title: Impact on abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.
abstract: We evaluated the impact of a strong CYP3A4 inhibitor, ketoconazole, and a strong inducer, rifampicin, on the pharmacokinetic (PK) exposure of abiraterone in two studies in healthy men. All subjects received 1,000 mg of abiraterone acetate on Days 1 and 14. Study A subjects (n = 20) received 400 mg ketoconazole on Days 11-16. Study B subjects (n = 19) received 600 mg rifampicin on Days 8-13. Serial PK sampling was done on Days 1 and 14. Study A: When given with ketoconazole, abiraterone exposure increased by 9% for maximum plasma concentration (Cmax ) and 15% for area under the plasma concentration-time curve from 0 to time of the last quantifiable concentration (AUClast ) and AUC from time 0 to infinity (AUC∞ ) compared to abiraterone acetate alone. Study B: When given with rifampicin, abiraterone exposure was reduced to 45% for Cmax and AUC∞ and to 42% for AUClast compared to abiraterone acetate alone. Ketoconazole had no clinically meaningful impact on abiraterone exposure. Rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be avoided or used with careful evaluation of clinical efficacy when administered with abiraterone acetate.
authors.affiliation: Janssen Research & Development, Clinical Pharmacology, Raritan, NJ, USA.
authors.forename: Apexa
authors.initials: A
authors.lastname: Bernard
authors.affiliation: Janssen Research & Development, Clinical Pharmacology, San Diego, CA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Vaccaro
authors.affiliation: Janssen Research & Development, Clinical Pharmacology, Raritan, NJ, USA.
authors.forename: Milin
authors.initials: M
authors.lastname: Acharya
authors.affiliation: Janssen Research & Development, Biometrics and Reporting, Raritan, NJ, USA.
authors.forename: James
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Janssen Research & Development, Preclinical Project Development, Beerse, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Monbaliu
authors.affiliation: Janssen Research & Development, Bioanalysis, Beerse, Belgium.
authors.forename: Ronald
authors.initials: R
authors.lastname: De Vries
authors.affiliation: Janssen Research & Development, Bioanalysis, Beerse, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Stieltjes
authors.affiliation: Janssen Research & Development, WC Clinical Oncology, Los Angeles, CA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Yu
authors.affiliation: Janssen Research & Development, WC Clinical Oncology, Los Angeles, CA, USA.
authors.forename: Namphuong
authors.initials: N
authors.lastname: Tran
authors.affiliation: Janssen Research & Development, Clinical Pharmacology, Titusville, NJ, USA.
authors.forename: Caly
authors.initials: C
authors.lastname: Chien
mesh_terms: D000069501:Abiraterone Acetate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001530:Belgium; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage* / Q000009:adverse effects; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004347:Drug Interactions; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010087:Oxides / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects; D013431:Sulfates / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D010087:Oxides; D013431:Sulfates; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000069501:Abiraterone Acetate; D007654:Ketoconazole; D012293:Rifampin
keywords: CYP3A4; abiraterone acetate; ketoconazole; pharmacokinetics; rifampicin