Population pharmacokinetic modeling and bioequivalence clinical trial simulations of niraparib plus abiraterone acetate administered as single-agent combination and dual-acting tablets plus prednisone for the treatment of metastatic castration-resistant prostate cancer
Alberto Russu (1), Anasuya Hazra (2*), Hui Tian (2), Nahor Haddish-Berhane (2), Juan Jose Perez Ruixo (3), Muriel Boulton (4)
(1) Janssen-Cilag SpA, Cologno Monzese, Italy; (2) Janssen R&D, Raritan, NJ; Janssen R&D, Spring House, PA; (3) Janssen-Cilag Spain, Madrid, Spain; (4) Janssen R&D, Beerse, Belgium. * At the time of study conduct. Current affiliation: Regeneron, Tarrytown, NY
Objectives: The combination of niraparib and abiraterone acetate (AA), a prodrug of abiraterone, targets two oncogenic drivers in patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib is a highly selective poly adenosine-diphosphate-ribose polymerase (PARP) inhibitor with potent anti–DNA-repair activity which targets homologous recombination repair (HRR) gene alterations [1], and abiraterone is an androgen biosynthesis inhibitor [2]. The fixed-dose combination of niraparib and AA as regular-strength dual-action tablets (RS-DAT; 200 mg niraparib/1000 mg AA) or as low-strength DAT (LS-DAT; 100 mg niraparib/1000 mg AA to allow for dose reduction of niraparib) plus 10 mg prednisone daily is currently under investigation for the treatment of patients with mCRPC.
The objectives of this analysis were to: (i) characterize the population pharmacokinetics (PPK) of niraparib and abiraterone, administered alone or in combination (either as single agents or as RS- and LS-DAT), and (ii) evaluate the probability of LS-DAT to meet bioequivalence (BE) criteria (90% confidence interval [CI] of geometric mean ratio [GMR] for both steady-state area under the plasma concentration-time curve over 24 hours [AUC0-24h,ss] and maximum concentration [Cmax,ss] within the 80% to 125% range) compared with the single-agent combination (SAC; niraparib 100 mg and 1000 mg AA) via clinical trial simulations.
Methods:
PPK modeling and covariate analysis using non-linear mixed-effect modelling in NONMEM [3] were conducted using pooled PK data from patients with mCRPC enrolled in the BEDIVERE, GALAHAD, QUEST, and MAGNITUDE studies, as well as in a study of relative bioavailability (BA) for LS-DAT and BE for RS-DAT (BA/BE study). In all studies except GALAHAD (where niraparib was given as monotherapy), AA plus prednisone (AAP) was given alone or in combination with niraparib. In total, 9935 niraparib plasma PK samples from 916 patients and 6289 abiraterone plasma PK samples from 954 patients were available.
BE clinical trial simulations comparing LS-DAT to SAC were performed based on the niraparib and abiraterone PPK models, using 1,000 replicates of the BA/BE cross-over study design (sample size of N=120), using R version 3.4.1 [4]. Individual PK profiles were generated by randomly sampling from the uncertainty in the estimation of structural and covariate parameters, the distribution of covariates in the BA/BE study, the interindividual variability, and the residual unexplained variability. The probability of demonstrating BE for LS-DAT compared with SAC was calculated as the proportion of simulated replicates in which BE criteria were met for both AUC0-24h,ss and Cmax,ss for both niraparib and abiraterone.
Results:
Niraparib and abiraterone PK were adequately described by an open 2-compartment model with linear elimination and sequential zero-first order absorption (with 2 transit compartments for abiraterone). For niraparib, identified covariates were creatinine clearance on oral clearance (CL); LS-DAT on zero-order drug release (D1) and apparent oral bioavailability (F1); HRR status on CL; race on first-order absorption rate constant (KA), intercompartmental clearance, and volume of distribution of the peripheral compartment. These covariate effects had no clinically relevant impact on niraparib exposure and therefore no dose adjustments by these covariates were warranted. For abiraterone, RS-DAT was a covariate of KA, D1, and F1, however, the magnitude of these covariate effects was not deemed clinically relevant.
Since the final abiraterone PPK model did not contain any effect of LS-DAT on absorption parameters (i.e., not retained due to large relative standard errors), a pre-final abiraterone PPK model that included effects of LS-DAT on KA (20% decrease versus SAC) and D1 (34% decrease versus SAC) was used for the simulated BE assessment of LS-DAT. Based on the simulations, the average geometric mean ratio for LS-DAT versus SAC was 88.2% and 88.7% for niraparib AUC0-24h,ss and Cmax,ss, respectively, and 100% and 98.7% for abiraterone AUC0-24h,ss and Cmax,ss, respectively. The probability of demonstrating BE for LS-DAT versus SAC was 96.4%.
Conclusions: The PPK analyses support the selected clinical dosage of 200 mg niraparib/1000 mg AA as RS-DAT (or 100 mg niraparib/1000 mg AA as LS-DAT for dose reduction of niraparib) plus 10 mg prednisone daily for the treatment of patients with mCRPC and HRR gene alterations.
References:
[1] Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: A poly (ADP-ribose) polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination. J Med Chem. 2015;58(8):3302-3314
[2] O'Donnell A, Judson I, Dowsett M, et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer. 2004 Jun 14;90(12):2317-2325
[3] NONMEM 7.3 Users Guide (1989-2011). Beal SL, Sheiner LB, Boeckmann AJ, and Bauer RJ (eds). Icon Development Solutions, Ellicott City, MD
[4] R Core Team (2017). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/