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

Abstract

AimsAbiraterone acetate, a prodrug of abiraterone (ABI), provides an efficient therapeutic option for metastatic castration‐resistant prostate cancer patients. ABI undergoes extensive metabolism in vivo and is transformed into active metabolites Δ4‐abiraterone (D4A) and 3‐keto‐5α‐abiraterone (5αA) as well as inactive metabolites abiraterone sulfate (A‐Sul) and abiraterone N‐oxide sulfate (A‐NO‐Sul). We aimed to examine the effect of polymorphisms in SLCO2B1, CYP3A4 and UGT1A4 on the pharmacokinetics of ABI and its metabolites.MethodsIn this study, 81 healthy Chinese subjects were enrolled and divided into two groups for fasted (n = 45) and fed (n = 36) studies. Plasma samples were collected after administering a 250 mg abiraterone acetate tablet followed by LC‐MS/MS analysis. Genotyping was performed on a MassARRAY system. The association between SLCO2B1, CYP3A4, UGT1A4 genotype and pharmacokinetic parameters of ABI and its metabolites was assessed.ResultsFood effect study demonstrated high fat meal remarkedly increased systemic exposure of ABI and its metabolites. The geometric mean ratio and 90% confidence interval of AUC0‐t and Cmax of ABI in fed state versus fasted state were 351.64% (286.86% – 431.04%) and 478.45% (390.01% – 586.94%), respectively, while the corresponding results were ranging from 145.11% to 269.42% and 150.10% to 478.45% for AUC0‐t and Cmax of ABI metabolites in fed state versus fasted state, respectively. The SLCO2B1 rs1077858 had a significant influence on AUC0‐t and Cmax, while seven other SLCO2B1 variants prolonged t1/2 of ABI under both fasted and fed conditions. As for ABI metabolites, the systemic exposure of D4A, A‐Sul and A‐NO‐Sul as well as the elimination of 5αA were significantly affected by SLCO2B1 polymorphisms. Polymorphisms in CYP3A4 and UGT1A4 did not significantly affect PK of ABI and its metabolites.ConclusionsPolymorphisms in SLCO2B1 were significantly related to the PK variability of ABI and its metabolites under both fasted and fed conditions.