Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment

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 x 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/mu L, >= 150,000/mu L). PK parameters included maximum concentration (C-max), area under the curve to last measured concentration (AUC(last)) and extrapolated to infinity (AUC(inf)). 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 C-max was 7% lower in patients with MHI versus NHF. Mean exposure (AUC(last), AUC(inf)) 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.