Abstract

Abiraterone acetate, the prodrug of the cytochrome P450 (CYP) C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration-resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values that were near or below the peak concentrations observed in patients with mCRPC (IC50 values: 1.3 - 3.0 μM, 1.6 - 2.9 μM, 0.044 - 0.15 μM, and 5.4 - 5.9 μM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted in 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again at 1 h after abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 h after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 124.99 (90% CI, 99.91 - 156.38) for Cmax and 146.45 (90% CI, 125.70 - 170.62) for AUClast. Exposure to M-III and M-IV was reduced by 10 to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo.