Abstract
SummaryNiraparib 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) of 14C–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 of 14C–radioactivity was slow, with t1/2 in plasma on average 92.5 h. Oral absorption of 14C–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.
Highlights
Niraparib (MK-4827) is a novel, investigational poly(ADPRibose) polymerase (PARP) inhibitor with antitumour effect in BRCA1 and BRCA2 mutated cancer cells [1, 2]
The Netherlands Cancer Institute, Amsterdam, The Netherlands 4 Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands hepatic pathways are comparably involved in excretion of niraparib and its metabolites
Oral absorption of 14C–niraparib was rapid, with niraparib concentrations peaking at 2.49 h, and reaching a mean maximum concentration of 540 ng/mL
Summary
Niraparib (MK-4827) is a novel, investigational poly(ADPRibose) polymerase (PARP) inhibitor with antitumour effect in BRCA1 and BRCA2 mutated cancer cells [1, 2]. A doseescalation study revealed that a daily dose of 300 mg is well tolerated, has favourable pharmacological properties and antitumour activity in a broad patient population regardless of biomarker status including BRCA1 and BRCA2 mutations [2]. Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have emphasised the importance of human absorption, metabolism and excretion (AME) studies in drug discovery and drug development, and Invest New Drugs (2017) 35:751–765 it is required for regulatory filing [6, 7]. This study determines the plasma concentration-time profiles of niraparib and its metabolites in humans by liquid chromatography – tandem mass spectrometry (LC-MS/MS)
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