title: Human mass balance study and metabolite profiling of14C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer.
abstract: Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status. This study evaluates the absorption, metabolism and excretion (AME) of14C-niraparib, administered to six patients as a single oral dose of 300 mg with a radioactivity of 100 μCi. Total radioactivity (TRA) in whole blood, plasma, urine and faeces was measured using liquid scintillation counting (LSC) to obtain the mass balance of niraparib. Moreover, metabolite profiling was performed on selected plasma, urine and faeces samples using liquid chromatography - tandem mass spectrometry (LC-MS/MS) coupled to off-line LSC. Mean TRA recovered over 504 h was 47.5% in urine and 38.8% in faeces, indicating that both renal and hepatic pathways are comparably involved in excretion of niraparib and its metabolites. The elimination of14C-radioactivity was slow, with t1/2in plasma on average 92.5 h. Oral absorption of14C-niraparib was rapid, with niraparib concentrations peaking at 2.49 h, and reaching a mean maximum concentration of 540 ng/mL. Two major metabolites were found: the known metabolite M1 (amide hydrolysed niraparib) and the glucuronide of M1. Based on this study it was shown that niraparib undergoes hydrolytic, and conjugative metabolic conversions, with the oxidative pathway being minimal.
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands. l.v.andel@nki.nl.
authors.forename: Lotte
authors.initials: L
authors.lastname: van Andel
authors.affiliation: Tesaro Inc., Waltham, MA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Tesaro Inc., Waltham, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Tesaro Inc., Waltham, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kansra
authors.affiliation: Tesaro Inc., Waltham, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Tesaro Inc., Waltham, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Hughes
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Tibben
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Gebretensae
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Lucas
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands.
authors.forename: M J X
authors.initials: MJX
authors.lastname: Hillebrand
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital / The Netherlands Cancer Institute and MC Slotervaart, P.O. Box 90440, 1006 BK, Amsterdam, The Netherlands.|Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes / Q000032:analysis* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007191:Indazoles / Q000032:analysis* / Q000494:pharmacology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010880:Piperidines / Q000032:analysis* / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000032:analysis / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry*; D011379:Prognosis
chemical_list: D002250:Carbon Radioisotopes; D007191:Indazoles; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C000615234:Carbon-14; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C545685:niraparib
keywords: ADME; Mass balance; Metabolites; Niraparib; Radiolabelled; TRA