Impact on abiraterone pharmacokinetics and safety: Open-label drug-drug interaction studies with ketoconazole and rifampicin.

Publisher: Wiley Country of Publication: United States NLM ID: 101572899 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2160-7648 (Electronic) Linking ISSN: 2160763X NLM ISO Abbreviation: Clin Pharmacol Drug Dev Subsets: MEDLINE

Publication: 2013- : Hoboken, NJ : Wiley
Original Publication: Thousand Oaks, Calif. : Sage Publications, c2012-

Abiraterone Acetate/*pharmacokinetics ; Cytochrome P-450 CYP3A/*metabolism ; Cytochrome P-450 CYP3A Inducers/*administration & dosage ; Cytochrome P-450 CYP3A Inhibitors/*administration & dosage ; Ketoconazole/*administration & dosage ; Rifampin/*administration & dosage; Abiraterone Acetate/administration & dosage ; Abiraterone Acetate/adverse effects ; Adolescent ; Adult ; Area Under Curve ; Belgium ; Biotransformation ; Cytochrome P-450 CYP3A Inducers/adverse effects ; Cytochrome P-450 CYP3A Inhibitors/adverse effects ; Drug Interactions ; Half-Life ; Healthy Volunteers ; Humans ; Ketoconazole/adverse effects ; Male ; Metabolic Clearance Rate ; Middle Aged ; Models, Biological ; Oxides/pharmacokinetics ; Rifampin/adverse effects ; Sulfates/pharmacokinetics ; Young Adult

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.
(© 2014, The American College of Clinical Pharmacology.)

Keywords: CYP3A4; abiraterone acetate; ketoconazole; pharmacokinetics; rifampicin

0 (Cytochrome P-450 CYP3A Inducers)
0 (Cytochrome P-450 CYP3A Inhibitors)
0 (Oxides)
0 (Sulfates)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)
EC 1.14.14.55 (CYP3A4 protein, human)
EM5OCB9YJ6 (Abiraterone Acetate)
R9400W927I (Ketoconazole)
VJT6J7R4TR (Rifampin)

Date Created: 20160430 Date Completed: 20180122 Latest Revision: 20181211

20231215

10.1002/cpdd.132

27128004