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

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) 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 t_1/2 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.

Keywords: ADME; Mass balance; Metabolites; Niraparib; Radiolabelled; TRA.

Fig. 1

Molecular structure of ¹⁴C-niraparib tosylate

Fig. 2

Mean (±SD) log-linear concentration-time profile of total radioactivity (niraparib-related compounds) in whole blood and plasma after a single dose of 300 mg ¹⁴C–niraparib to patients with advanced cancer (n = 6)

Fig. 3

Mean (±SD) cumulative recovered radioactivity in excreta after a single dose of 300 mg ¹⁴C–niraparib to patients with advanced cancer (n = 6)

Fig. 4

Radiochromatogram of plasma screening samples collected 4 h (a) and 48 h (b) post-dose. Note that the scale of the y-axis is different in each radiochromatogram.

Fig. 5

Radiochromatogram of urine screening samples collected 0-24 h (a) and 24-72 h (b) post-dose. Note that the scale of the y-axis is different in each radiochromatogram.

Fig. 6

Radiochromatogram of faeces screening samples collected 0-24 h (a), 24-72 h (b) and 72-144 h (c) post-dose. Note that the scale of the y-axis is different in each radiochromatogram.

Fig. 7

Mean log-linear concentration-time profiles of radioactive metabolites found in plasma between 0 and 168 h

Fig. 8

Summary of niraparib metabolite excretion through 144 h after a single oral dose of ¹⁴C-niraparib

Fig. 9

Proposed metabolic pathway of niraparib in humans