Open-Label, Phase I, Pharmacokinetic Studies in Healthy Chinese Subjects to Evaluate the Bioequivalence and Food Effect of a Novel Formulation of Abiraterone Acetate Tablets

Abstract

Abiraterone acetate tablets (I)(N-AbA) is a novel tablet co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). This study aimed to compare the pharmacokinetics, bioequivalence, safety, and food effects of N-AbA with the reference ZYTIGA ® (R-AbA) in healthy Chinese male subjects. Patients and Methods: This study was conducted in three parts. Part I was an open, doseescalation trial conducted in 16 Chinese healthy males; Part II was a randomized, open-label, 2 × 4 crossover, single-dose bioequivalence trial conducted in 36 subjects; Part III was a randomized, 3 × 3 crossover trial conducted on 24 volunteers to investigate the effect of food on the pharmacokinetics of N-AbA. Results:The exposure (AUC 0-∞ ) and maximum concentration (C max ) of abiraterone and excipient SNAC were linear in the range of 75-450 mg dose. The bioavailability of N-AbA 300 mg was equivalent to that of R-AbA 1000 mg. The drug exposure of prednisone and prednisolone was not affected by SNAC co-administration. The C max of orally administered abiraterone as R-AbA in a modified fed state was 5.9 times and AUC 0-∞ was 4.3 times, respectively, higher than those in of orally administered abiraterone as N-AbA in a high-fat diet. The C max and AUC 0-∞ of orally administered abiraterone as N-AbA on a high-fat diet were 2.2 times and 2 times, respectively, higher than those on a fasting state. All adverse events reported in the three parts of the study were grade 1 or 2, and no serious adverse events were reported. Conclusion: These three Phase I trials showed that N-AbA and excipient SNAC had excellent linear pharmacokinetic characteristics. A single dose of N-AbA 300 mg was bioequivalent to R-AbA 1000 mg in healthy subjects under fasting conditions. Meanwhile, SNAC had no effect on the pharmacokinetics of prednisone and prednisolone. The effect of food on N-AbA was significantly lower than that on R-AbA.

Effect of food and polymorphisms in SLCO2B1, CYP3A4 and UGT1A4 on pharmacokinetics of abiraterone and its metabolites in Chinese volunteers

“…Such discrepancy in the fold change for systemic exposure might be due to the different ethnicity and distinct food composition. The magnitude of the food effect in our study was in good agreement with a previous study carried out in Chinese volunteers 27 . As is known, dietary fat could increase the level of endogenous bile salt in the gut, improve the dissolution rate of ABI as a lipophilic drug and therefore result in superior intestinal absorption 31 .…”

“…5,6 In line with previous studies, prandial status showed extensive effects on the PK of ABI in a Chinese population. It was also reported that fed condition increased C max of ABI in multiple races by 2.2 to 16.8-fold and AUC by 2.0 to 9.7-fold relative to those in fasted condition, [21][22][23][24][25][26][27][28][29][30] respectively. Such discrepancy in the fold change for systemic exposure might be due to the different ethnicity and distinct food composition.…”

“…The magnitude of the food effect in our study was in good agreement with a previous study carried out in Chinese volunteers. 27 As is known, dietary fat could increase the level of endogenous bile salt in the gut, improve the dissolution rate of ABI as a lipophilic drug and therefore result in superior intestinal absorption. 31 Interestingly, a previous study in which AA was administered 20 min after the low-fat meal demonstrated similar food effect.…”