Crossover pharmacokinetics (PK) study to assess oral administration of abiraterone acetate capsule and tablet formulations in fasted and fed states in patients with prostate cancer

Abstract

5168 Background: Abiraterone acetate (A) is an oral compound with metabolites that selectively inhibit CYP 17(17OH/ 17,20 lyase), blocking adrenal androgen synthesis and exhibiting anti-tumor activity in castration resistant prostate cancer (CRPC). Methods: Patients were divided into fed or fasted groups, and treated at 1000mg/day as a single dose in either capsule or tablet formulation on day 1, then the opposite formulation one week later on day 8, and from day 15, continuous dosing of 1000mg of the tablet formulation. PK samples were taken pre-dose and 1, 2, 4, 6, 8, 24, 48 and 72 hr post dose on days 1 and 8. Statistical analysis employed a two- period crossover model, using non-compartmental analysis. Results: A was well tolerated and side effects readily managed by mineralocorticoid antagonists. Overall 31 patients were enrolled, with PK results from 19 patients presented here. Area under the curve (AUC), was not significantly different between the two formulations for either the fed (p=0.412) or the fasted (p=0.334) states. However, there was a significantly higher mean Cmax in the fed state compared with the fasted state for both formulations: mean Cmax (nmol/l) capsules: (fed) 1469 vs (fasted) 286, p= 0.005; mean Cmax (nmol/l) tablets: (fed) 1573 vs (fasted) 324, p=0.004. AUC was also significantly higher in the fed state than in the fasted state for both formulations: AUC (hr*nmol/l) capsules: (fed) 10978 vs (fasted) 3249, p<0.001; AUC (hr*nmol/l) tablets: (fed) 10782 vs (fasted) 3090, p<0.001. Antitumor activity was observed as indicated by PSA declines, radiological responses, and symptomatic benefit. Conclusions: Similar Cmax and AUC were observed after administration of capsule and tablet formulations of A irrespective of fed or fasted state, suggesting bioequivalence. However both of these PK parameters were significantly higher in fed patients. Pharmacokinetic parameters comparing capsules with tablets Tmac (hr) Cmax (nmol/l) Terminal half life (hr) AUC (hr*nmol/l) Total body clearance (L/hr) Volume of distribution (L) Capsules (Fed) Mean 3.491 1469 13.8 10978 307 6254 Standard deviation (SD) 2.25 1156 2.35 3602 194 4686 Tablets (fed) Mean 3.176 1573 16.8 10782 341 7546 SD 1.69 1218 6.17 4732 255 4251 Capsules (fasted) Mean 3.068 286 16.8 3249 2094 30566 SD 1.64 161 11.4 2005 2846 35337 Tablets (fasted) Mean 2.098 324 16.7 3090 1308 35566 SD 0.70 215 10.4 2127 866 44766 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cougar Biotechnology Cougar Biotechnology