Pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment

Mehmet Akce,Ashley Milton,Reginald Ewesuedo,Stefan Zajic,Sarina A Piha-Paul,Patricia L Judson,Zhi-Yi Zhang,Yongqiang Tang,Peng Pan,Anthony El-Khoueiry,Divya Gupta,Cindy L O’Bryant,Emeline Bacque

doi:10.1007/s00280-021-04329-8

Abstract

PurposeThe purpose of this study is to characterize niraparib pharmacokinetics (PK) and safety in patients with normal hepatic function (NHF) versus moderate hepatic impairment (MHI).MethodsPatients 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.ResultsIn 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.ConclusionThese findings support adjusting the 300 mg niraparib starting dose to 200 mg QD in patients with MHI.Trial registrationNCT03359850; registered December 2, 2017

Highlights

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in several countries and regions, including the USA, Canada, Japan, and EU for the first- or second-line maintenance treatment of adult patients with advanced or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy [1, 2]
Nine patients were assigned to the normal hepatic function (NHF) group and eight patients to the moderate hepatic impairment (MHI) group, all of whom were included in the PK and safety population of the PK phase
The pattern of treatment-emergent adverse events (TEAEs) observed in this study with niraparib is consistent with data from previous Phase 3 registrational trials (NOVA, PRIMA, and QUADRA) [4, 14,15,16], regardless of hepatic function

Summary

Introduction

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in several countries and regions, including the USA, Canada, Japan, and EU for the first- or second-line maintenance treatment of adult patients with advanced or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy [1, 2]. In the USA, niraparib is indicated for the treatment of adult patients with advanced, homologous recombination deficiency (HRD)-positive ovarian, fallopian tube, or primary peritoneal cancer who have received ≥ 3 prior chemotherapy regimens. Over 21 days following administration of a single oral 300 mg dose of radiolabeled niraparib in patients with cancer who had adequate renal and hepatic function, 47.5% of the administered dose was recovered in urine and 38.8% in feces, indicating that both renal and hepatobiliary pathways are involved in the elimination of niraparib and its metabolites [7]

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