Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment

Abstract

Purpose: The purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI).

Methods: Patients with advanced solid tumors were stratified by NHF or MHI (National Cancer Institute-Organ Dysfunction Working Group criteria [bilirubin > 1.5-3 × upper limit of normal and any aspartate aminotransferase elevation]). In the PK phase, all patients received one 300 mg dose of niraparib. In the extension phase, patients with MHI received niraparib 200 mg daily; patients with NHF received 200 or 300 mg based on weight (< 77 kg, ≥ 77 kg)/platelets (< 150,000/µL, ≥ 150,000/µL). PK parameters included maximum concentration (Cmax), area under the curve to last measured concentration (AUClast) and extrapolated to infinity (AUCinf). Safety was assessed in both phases. Exposure-response (E-R) modeling was used to predict MHI effects on exposure and safety of niraparib doses ≤ 200 mg or 300/200 mg or 200/100 mg weight/platelet regimens.

Results: In the PK phase (NHF, n = 9; MHI, n = 8), mean niraparib Cmax was 7% lower in patients with MHI versus NHF. Mean exposure (AUClast, AUCinf) was increased by 45% and 56%, respectively, in patients with MHI without impacting tolerability. In the extension phase (NHF, n = 8; MHI, n = 7), the overall safety profile was consistent with previous trials. In patients with MHI, E-R modeling predicted niraparib 200 mg reduced Grade ≥ 3 thrombocytopenia incidence, whereas a 200/100 mg regimen yielded exposures below efficacy-associated levels in 15% of patients.

Conclusion: These findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI.

Trial registration: NCT03359850; registered December 2, 2017.

Keywords: Dosing; Hepatic impairment; Niraparib; Pharmacokinetics; Safety.

Conflict of interest statement

MA: reports research funding to their institution from Tesaro, RedHill Biopharma Ltd., Polaris, Bristol-Myers Squibb/Ono Pharmaceutical, Xencor, Merck Sharp and Dohme, Eisai; consultant or advisory role for Eisai, Ipsen, GlaxoSmithKline, Exelixis, and QED.

AEK: reports research funding from AstraZeneca, Astex Pharmaceuticals, and Merck; consultant or advisory role for and received honoraria from Agenus, AstraZeneca, Bayer, Bristol-Myers Squiib, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck, Pieris Pharmaceuticals, Roche/Genentech, and QED.

SAP-P: reports research funding to their institution from AbbVie, ABM Therapeutics, Acepodia, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical, Curis, Daichii Sankyo, Eli Lilly, ENB Therapeutics, FivePrime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma, Incyte, Jacobio Pharmaceuticals, MedImmune, Medivation, Merck Sharp & Dohme, Novartis, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, RAPT Therapeutics, Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, TransThera Biosciences, NCI/NIH P30CA016672 Core Grant.

EB, PP, RE, DG, YT, PLJ, SZ: employees of and hold shares/options in GlaxoSmithKline.

AM and Z-YZ: employees of GlaxoSmithKline at the time of study and manuscript development.

CLO: reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline; personal fees from AstraZeneca and Genentech; research grants from Pfizer.

© 2021. The Author(s).

Figures

Fig. 1

Niraparib a Cmax (ng/mL) box plot, b mean concentration–time profiles, c AUClast box plot and d AUCinf box plot following single-dose administration by hepatic function group. a, c, and d solid lines represent mean values; dashed lines represent median values; upper and lower boxes represent middle two quartiles (i.e., 50%); whiskers indicate minimum and maximum values. a Circle indicates outlier value in normal hepatic function group. b Error bars indicate ± SD. AUCinf, area under the plasma concentration–time curve from time 0 extrapolated to infinity; AUClast area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration; Cmax observed maximum plasma concentration; SD standard deviation

Fig. 2

a Comparison of predicted probabilities of Grade ≥ 3 thrombocytopenia for patients with NHF and MHI and b simulated AUCss in patients with MHI and model-predicted AUCss in patients from PRIMA study. a Closed circles represent the mean of probability of Grade ≥ 3 thrombocytopenia and error bars represent the 95% prediction intervals. b Percentages represent the portion of virtual patients with AUCss below the range of AUCss in the PRIMA study. AUCss was based on starting dose. AUCss steady-state area under concentration–time curve, MHI moderate hepatic impairment, NHF normal hepatic function, W&P: X/Y mg = X mg if baseline body weight ≥ 77 kg and baseline platelet count ≥ 150,000/µL and Y mg if baseline body weight < 77 kg or baseline platelet count < 150,000/µL