Human mass balance study and metabolite profiling of 14C-niraparib, a novel poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor, in patients with advanced cancer

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.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects

“…A plasma sample (0–120 h) was obtained by pooling plasma at each time point of a volume proportional to the time interval used for calculating the area under the concentration–time curve (AUC) (AUC 0–120 h pool) for each subject. Moreover, three plasma samples at time periods 0–0.0833 h, 0.133–2 h and 4–120 h were obtained by pooling equal volumes of plasma across individuals at the same time point 10–12 . Urine samples (0–168 h) were pooled at an equal percentage of collection volume to obtain one pooled sample for each subject.…”

Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy

“…Moreover, pharmacokinetics differs from one PARPi to another. For example, niraparib is not metabolized by hepatic cytochromes and has less potential for drug-drug interactions [ 43 , 44 ]. Furthermore, the absorption is not influenced by food [ 42 ].…”

“…Studies with radiolabeled niraparib have shown a recovery of 47.5% of the drug in urines and 38.8% in feces [ 44 ].…”

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients

“…The t ½ of total 14 C-radioactivity was longer than the t ½ of 14 C-niraparib, which further confirms metabolite formation. Metabolites have been identified and quantified previously [ 16 ]. Besides niraparib, the main moiety in circulation, the amide-hydrolysed niraparib metabolite (M1) and its glucuronide (M10) were also substantially present in circulation.…”

“…A mass balance study in humans using radiolabelled niraparib investigated the amount of niraparib and niraparib-related compounds excreted in urine and in faeces [ 16 ]. Of the total dose orally administered, approximately 90% was recovered in excreta, with approximately 20% recovered as the parent compound in faeces.…”