Chemical formula: C₁₉H₂₀N₄O Molecular mass: 320.396 g/mol PubChem compound: 24958200
Niraparib is an inhibitor of poly(ADP-ribose) polymerase (PARP) enzymes, PARP-1 and PARP-2, which play a role in DNA repair. In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was observed in tumour cell lines with or without deficiencies in the BReast CAncer (BRCA) 1 and 2 tumour suppressor genes. In orthotopic high-grade serous ovarian cancer patient-derived xenograft tumours (PDX) grown in mice, niraparib has been shown to reduce tumour growth in BRCA 1 and 2 mutant, BRCA wild-type but homologous recombination (HR) deficient, and in tumours that are BRCA wild-type and without detectable HR deficiency.
Following a single-dose administration of 300 mg niraparib under fasting conditions, niraparib was measurable in plasma within 30 minutes and the mean peak plasma concentration (Cmax) for niraparib was reached in about 3 hours [804 ng/mL (% CV:50.2%)]. Following multiple oral doses of niraparib from 30 mg to 400 mg once daily, accumulation of niraparib was approximately 2 to 3 folds.
The systemic exposures (Cmax and AUC) to niraparib increased in a dose-proportional manner when the dose of niraparib increased from 30 mg to 400 mg. The absolute bioavailability of niraparib is approximately 73%, indicating minimal first pass effect.
A concomitant high-fat meal did not significantly affect the pharmacokinetics of niraparib after administration of 300 mg of niraparib.
Niraparib was moderately protein bound in human plasma (83.0%), mainly with serum albumin. In a population pharmacokinetic analysis of niraparib, the Vd/F was 1,074 L in cancer patients, indicating extensive tissue distribution of niraparib.
Niraparib is metabolised primarily by carboxylesterases (CEs) to form a major inactive metabolite, M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the major circulating metabolites.
Following a single oral 300-mg dose of niraparib, the mean terminal half-life (t1⁄2) of niraparib ranged from 48 to 51 hours (approximately 2 days). In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.
Niraparib is eliminated primarily through the hepatobiliary and renal routes. Following an oral administration of a single 300-mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) of the dose was recovered in urine and feces over 21 days. Radioactive recovery in the urine accounted for 47.5% (range 33.4% to 60.2%) and in the feces for 38.8% (range 28.3% to 47.0%) of the dose. In pooled samples collected over 6 days, 40.0% of the dose was recovered in the urine primarily as metabolites and 31.6% of the dose was recovered in the feces primarily as unchanged niraparib.
In the population pharmacokinetic analysis of data from clinical studies in patients, pre-existing mild (CLCr <90 - ≥60 ml/min) and moderate (CLCr <60 - ≥30 mL/min) renal impairment did not influence the clearance of niraparib. No patients with pre-existing severe renal impairment or end-stage renal disease undergoing hemodialysis were identified in clinical studies.
In the population pharmacokinetic analysis of data from clinical studies in patients, pre-existing mild and moderate hepatic impairment did not influence the clearance of niraparib. The pharmacokinetics of niraparib have not been assessed in patients with severe hepatic impairment.
Population pharmacokinetic analyses indicated that age, weight and race had no significant impact on the pharmacokinetics of niraparib.
No studies have been conducted to investigate the pharmacokinetics of niraparib in paediatric patients.
In vitro, niraparib inhibited the dopamine transporter DAT at concentration levels below human exposure levels. In mice, single doses of niraparib increased intracellular levels of dopamine and metabolites in cortex. Reduced locomotor activity was seen in one of two single dose studies in mice. The clinical relevance of these findings is not known. No effect on behavioural and/or neurological parameters have been observed in repeat-dose toxicity studies in rats and dogs at estimated CNS exposure levels similar to or below expected therapeutic exposure levels.
In repeat-dose oral toxicity studies, niraparib was administered daily for up to 3 months' duration in rats and dogs. The major primary target organ for toxicity in both species was the bone marrow, with associated changes in peripheral haematology parameters. Additionally, decreased spermatogenesis was seen in both species. These findings occurred at exposure levels below those seen clinically, and were largely reversible within 4 weeks of cessation of dosing.
Niraparib was not mutagenic in a bacterial reverse mutation assay (Ames) test but was clastogenic in an in vitro mammalian chromosomal aberration assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of niraparib and indicates potential for genotoxicity in humans.
Reproductive and developmental toxicity studies have not been conducted with niraparib.
Carcinogenicity studies have not been conducted with niraparib.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
