Pharmacokinetics and safety following a single oral dose of niraparib in patients with moderate hepatic impairment

Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with 33 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin >1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (C ), area under the concentrationtime curve calculated to last measured concentration (AUC ), and extrapolated to infinity (AUC ). PK parameters were determined using a noncompartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib C was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUC and AUC increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population.