tween 30 and 59 mL/min) showed approximately 15% and 32% higher steady-state AUC, respectively, compared to patients with normal renal function (N=143; CLcr greater than or equal to 90 mL/min). The pharmacokinetic characteristics of rucaparib in patients with CLcr less than 30 mL/min or patients on dialysis are unknown.
Hepatic Impairment
Based on population pharmacokinetic analyses, no apparent pharmacokinetic difference was observed in 34 patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin between 1.0 to 1.5 times ULN and any AST) who received Rubraca 600 mg twice daily as compared to patients with normal hepatic function (N=337). The pharmacokinetic characteristics of rucaparib in patients with moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN) are unknown.
CYP Enzyme Polymorphism
Based on population pharmacokinetic analyses, steady-state concentrations following rucaparib 600 mg twice daily did not differ significantly across CYP2D6 or CYP1A2 genotype subgroups.
Drug Interaction Studies
Effects of Other Drugs on Rucaparib
In vitro, rucaparib had a low metabolic turnover rate in human liver microsomes, and was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. In vitro, rucaparib was shown to be a substrate of P-gp and BCRP, but not a substrate of renal uptake transporters OAT1, OAT3, and OCT2, or hepatic transporters OATP1B1 and OATP1B3.
Concomitant treatment with proton pump inhibitors has no clinically meaningful change in steady-state exposures.
Effect of Rucaparib on Other Drugs
Effect of rucaparib on other drugs has not been studied in humans. Rucaparib reversibly inhibited CYP1A2, CYP2C19, CYP2C9, and CYP3A, and to a lesser extent CYP2C8, CYP2D6, and UGT1A1. Rucaparib induced CYP1A2, and down regulated CYP2B6 and CYP3A4 in human hepatocytes at clinically relevant exposures. Rucaparib was a potent inhibitor of MATE1 and MATE2-K, and a moderate inhibitor of OCT1. Weak inhibition was observed at ultra-therapeutic concentration (300 μM) of rucaparib for MRP4, OATP1B1, OATP1B3, OAT1, and OAT3. No inhibition was observed for MRP2, MRP3, or BSEP. Rucaparib was an inhibitor of BCRP and P-gp efflux transporters with IC50 of 55 μM and 283 μM, respectively.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with rucaparib.
Rucaparib was mutagenic in a bacterial reverse mutation (Ames) test, and clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes. The clastogenic response in mitotically-stimulated cells was anticipated based on the mechanism of action of rucaparib and indicates potential genotoxicity in humans.
Fertility studies with rucaparib have not been conducted. In 3-month repeat-dose general toxicology studies, rucaparib had no effects on male and female reproductive organs at doses up to 100 mg/kg/day and 20 mg/kg/day in rats and dogs, respectively. These dose levels resulted in systemic exposures of approximately 0.3 and 0.09 times the human exposure (AUC0-24h), respectively, at the recommended dose.
14 CLINICAL STUDIES
The efficacy of Rubraca was investigated in 106 patients in two multicenter, single-arm, open-label clinical trials, Study 1 and Study 2, in patients with advanced BRCA-mutant ovarian cancer who had progressed after 2 or more prior chemothera |
