content of the meal from fat) did not significantly affect the pharmacokinetics of niraparib.
Distribution
Niraparib is 83.0% bound to human plasma proteins. The average (±SD) apparent volume of distribution (Vd/F) was 1220 (±1114) L. In a population pharmacokinetic analysis, the Vd/F of niraparib was 1074 L in cancer patients.
Elimination
Following multiple daily doses of 300 mg niraparib, the mean half-life (t1/2) is 36 hours. In a population pharmacokinetic analysis, the apparent total clearance (CL/F) of niraparib was 16.2 L/h in cancer patients.
Metabolism
Niraparib is metabolized primarily by carboxylesterases (CEs) to form a major inactive metabolite, which subsequently undergoes glucuronidation.
Excretion
Following administration of a single oral 300 mg dose of radio-labeled niraparib, the average percent recovery of the administered dose over 21 days was 47.5% (range 33.4% to 60.2%) in urine, and 38.8% (range 28.3% to 47.0%) in feces. In pooled samples collected over 6 days, unchanged niraparib accounted for 11% and 19% of the administered dose recovered in urine and feces, respectively.
Specific Populations
Age (18 to 65 years old), race/ethnicity, and mild to moderate renal impairment had no clinically significant effect on the pharmacokinetics of niraparib.
The effect of severe renal impairment or end-stage renal disease undergoing hemodialysis on the pharmacokinetics of niraparib is unknown.
The effect of moderate or severe hepatic impairment on the pharmacokinetics of niraparib is unknown.
Drug Interaction Studies
No formal drug interaction studies have been performed with ZEJULA.
In Vitro Studies
Inhibition of CYPs: Neither niraparib nor the major primary metabolite M1 is an inhibitor of CYPA2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
Induction of CYPs: Neither niraparib nor M1 is a CYP3A4 inducer. Niraparib weakly induces CYP1A2 in vitro.
Substrate of CYPs: Niraparib is a substrate of carboxylesterases (CEs) and UDP-glucuronosyltransferases (UGTs) in vivo.
Inhibition of transporter systems: Niraparib is a weak inhibitor of BCRP, but does not inhibit P-gp or BSEP. The M1 metabolite is not an inhibitor of P-gp, BCRP, or BESP. Neither niraparib nor M1 is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2).
Substrate of transporter systems: Niraparib is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Niraparib is not a substrate of bile salt export pump (BSEP). The M1 metabolite is not a substrate of P-gp, BCRP, or BESP. Neither niraparib nor M1 is a substrate of organic anion transport polypeptide 1B1 (OATP1B1), 1B3 (OATP1B3), or organic cation transporter 1 (OCT1), organic anion transporter 1 (OAT1), 3 (OAT3), or organic cation transporter 2 (OCT2).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with niraparib.
Niraparib 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. Niraparib was not mutagenic in a bacterial reverse mutatio |
