Related Experiment Video
Updated: May 25, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Population Pharmacokinetics of Niraparib/Abiraterone Acetate Administered as Single-Agent Combination and Dual-Acting
Alberto Russu1,2, Anasuya Hazra3,4, Hui Tian3
1Johnson & Johnson, Viale Fulvio Testi 280/6, 20126, Milan, Italy. arussu@its.jnj.com.
Introduction:
Use 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.
Methods:
PPK 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.
Results:
Niraparib 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.
Conclusion:
PPK 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.
Insights
Population pharmacokinetics of niraparib and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) support the fixed-dose combination. The study found no clinically relevant impact of covariates on niraparib exposure, supporting current dosing for mCRPC treatment.
Area of Science:
- Pharmacokinetics
- Oncology
- Drug Development
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) treatment targets HRR gene alterations and the androgen-receptor axis.
- Niraparib and abiraterone acetate (AA) combination therapy is available in fixed-dose dual-action tablets (DATs).
- Regular-strength DAT (RS-DAT) and low-strength DAT (LS-DAT) allow for different niraparib dosing.
Purpose of the Study:
- To characterize the population pharmacokinetics (PPK) of niraparib and abiraterone.
- To evaluate the impact of covariates on drug exposure in patients with mCRPC.
- To support the clinical dosage of niraparib/AA combination therapy.
Main Methods:
- Non-linear mixed-effect modeling was used for PPK analysis.
- Pooled pharmacokinetic data from multiple clinical trials (BEDIVERE, GALAHAD, QUEST, MAGNITUDE) were analyzed.
- Plasma samples from 916 patients for niraparib and 954 patients for abiraterone were included.
Main Results:
- Niraparib and abiraterone pharmacokinetics were described by a two-compartment model.
- Covariates like creatinine clearance and HRR status affected niraparib clearance but not clinically significantly.
- Abiraterone bioavailability was slightly affected by RS-DAT, but not to a clinically relevant extent.
Conclusions:
- Population pharmacokinetic analyses support the current clinical dosage of RS-DAT (200 mg niraparib/1000 mg AA) plus prednisone for mCRPC.
- No dose adjustments for niraparib are warranted based on identified covariates.
- The findings support the efficacy and safety of the niraparib/AA combination in mCRPC patients with HRR gene alterations.
Related Concept Videos
01:23Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
A study on guinea pigs examined the...
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists