Population Pharmacokinetics of Niraparib/Abiraterone Acetate Administered as Single-Agent Combination and Dual-Acting Tablets Plus Prednisone for Metastatic Castration-Resistant Prostate Cancer.

introductionUse of niraparib and abiraterone acetate (AA; abiraterone prodrug) in patients with metastatic castration-resistant prostate cancer (mCRPC) targets two oncogenic drivers: homologous recombination repair (HRR) gene alterations and the androgen-receptor axis. Fixed-dose niraparib/AA combination is available as regular-strength dual-action tablets (RS-DAT; 200 mg/1000 mg) and low-strength DAT (LS-DAT; 100 mg/1000 mg, enabling niraparib dose reduction). We characterized the population pharmacokinetics (PPK) of niraparib and abiraterone, administered alone or in combination, in patients with mCRPC.

methodsPPK modeling and covariate analysis using a non-linear mixed-effect modeling approach were conducted using pooled PK data from patients with mCRPC enrolled in the BEDIVERE (NCT02924766), GALAHAD (NCT02854436), QUEST (NCT03431350), and MAGNITUDE (NCT03748641) studies and in a study of relative bioavailability for LS-DAT and bioequivalence for RS-DAT. In all but GALAHAD (niraparib monotherapy), AA + prednisone was given alone or with niraparib. Overall, 9935 and 6289 niraparib and abiraterone plasma PK samples from 916 and 954 patients, respectively, were available.

resultsNiraparib and abiraterone PK were adequately described by an open two-compartment disposition model with linear elimination, with a zero-order rate of drug release into the depot compartment followed by first-order absorption (via two transit compartments for abiraterone) into the central compartment. For niraparib, identified covariates were creatinine clearance on apparent oral clearance; LS-DAT on zero-order drug-release duration and apparent oral bioavailability; HRR status on apparent oral clearance; race on first-order absorption-rate constant, intercompartmental clearance, and peripheral compartment volume of distribution. Covariate effects had no clinically relevant impact on niraparib exposure, warranting no dose adjustments. For abiraterone, RS-DAT was the only newly identified covariate on apparent oral bioavailability, first-order absorption-rate constant, and zero-order drug-release duration; however, effect magnitude was deemed not clinically relevant.

conclusionPPK analyses support the selected clinical dosage of RS-DAT (200-mg niraparib/1000-mg AA) plus 10-mg prednisone daily for treating patients with mCRPC and HRR gene alterations.