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.

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

“…Abiraterone acetate and abiraterone sulfate were predicted to have K i values (inhibition constant = 0.5 Â IC 50 ) below 1 mM, which suggest high in vitro potency to cause in vivo drug interaction of at least two-fold (Obach et al, 2005). In a previous study, C max of abiraterone, abiraterone sulfate, and N-oxide abiraterone sulfate were reported to be approximately 0.37 mM, 25 mM, and 9.2 mM, respectively, after a single-dose administration of 1000 mg of abiraterone acetate to healthy volunteers (Bernard et al, 2015). The calculated R values (= 1 + [I] /K i ]) were greater than 1.1 for abiraterone and its metabolites, thus pointing toward the need for a clinical study to assess the interaction further.…”

“…The small decreases in metabolite concentrations suggest that their formation was minimally affected by CYP2C8 inhibition caused by abiraterone. Although the enzymes involved in the metabolism of M-IV and M-III have not been identified, it has been reported that clearance of M-IV and M-III is inducible by rifampicin (Bernard et al, 2015;Jaakkola et al, 2006a), suggesting that CYP450s regulated by the pregnane X receptor gene may play a role (e.g., CYP3A4, CYP2C family). Considering the overall effect based on exposures to the total active compounds (sum of pioglitazone, M-III, and M-IV), it is probable that the net effect of abiraterone is a slight increase in the efficacy of pioglitazone by approximately 26% only.…”

A dose finding clinical trial of cabozantinib (XL184) administered in combination with abiraterone acetate in metastatic castration‐resistant prostate cancer

“…The pharmacokinetics of cabozantinib are readily altered by agents that significantly inhibit or induce CYP3A4 activity . Systemic exposure to abiraterone was decreased by 55% when given to subjects that had been pretreated with the strong CYP3A4 inducer rifampin but not significantly affected when coadministered with the strong CYP3A4 inhibitor ketoconazole . The plasma pharmacokinetics of erlotinib, an approved anticancer drug for which CYP3A4 metabolism represents a prominent route of its elimination, was not affected by the coadministration of cabozantinib in a phase I study in patients with solid tumors .…”

The Effect of Food on the Absorption of Abiraterone Acetate from a Fine Particle Dosage Form: A Randomized Crossover Trial in Healthy Volunteers

“…The AA tablets should be swallowed whole with water and should not be crushed or chewed [7]. Several studies have investigated the effect of food on AA absorption and bioavailability [8][9][10][11][12] and established that consumption of a high-fat meal before administration of the originator AA (OAA) formulation markedly increases abiraterone absorption [9,10,12].…”