Rucaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP-1, PARP-2, and PARP-3, which play a role in DNA repair. In vitro studies have shown that rucaparib-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 rucaparib-induced cytotoxicity was observed in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.
12.2 Pharmacodynamics
The pharmacodynamic response of rucaparib has not been characterized.
Cardiac Electrophysiology
The effect of multiple doses of Rubraca on QTc interval was eva luated in an open-label single-arm study in 56 patients with solid tumors who were administered continuous doses of Rubraca ranging from 40 mg once daily (0.03 times the approved recommended dosage) to 840 mg twice daily (1.4 times the approved recommended dosage). The mean QTcF increase from baseline (90% confidence interval [CI]) in population pharmacokinetics estimated 95thpercentile Cmax (3019 ng/mL) at steady state of 600 mg rucaparib twice daily was 14.9 msec (11.1-18.7 msec).
12.3 Pharmacokinetics
All pharmacokinetics of rucaparib were characterized in patients with cancer. Rucaparib demonstrated linear pharmacokinetics over a dose range from 240 to 840 mg twice daily with time-independence and dose-proportionality. The mean steady-state rucaparib Cmax was 1940 ng/mL (54% coefficient of variation [CV]) and AUC0-12h was 16900 h·ng/mL (54% CV) at the approved recommended dosage. Accumulation was 3.5 to 6.2 fold. Median terminal half-life (T1/2) was 17 hours following a single intravenous dose of 12 to 40 mg rucaparib.
Absorption
The median Tmax was 1.9 hours at the approved recommended dosage. The mean absolute bioavailability of rucaparib immediate-release tablet was 36% with a range from 30% to 45%.
Following a high-fat meal, the Cmax was increased by 20% and AUC0-24h was increased by 38%, and Tmax was delayed by 2.5 hours, as compared to dosing under fasted conditions [see Dosage and Administration (2.2)].
Distribution
Rucaparib had a steady-state volume of distribution of 113 L to 262 L following a single intravenous dose of 12 mg to 40 mg rucaparib.
In vitro, the protein binding of rucaparib was 70% in human plasma at therapeutic concentrations. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.83.
Elimination
The mean terminal T1/2 of rucaparib was 17 to 19 hours, following a single oral dose of 600 mg rucaparib. The apparent clearance ranged from 15.3 to 79.2 L/hour, following continuous 600 mg rucaparib orally twice daily. The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg.
Metabolism
In vitro, rucaparib was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4.
Specific Populations
Age, Race, and Body Weight
Based on population pharmacokinetic analyses, age, race, and body weight did not have a clinically significant effect on rucaparib exposure.
Renal Impairment
In patients who received Rubraca 600 mg twice daily, those with mild renal impairment (N=148; CLcr between 60 and 89 mL/min, as estimated by the Cockcroft-Gault method) and those with moderate renal impairment (N=72; CLcr be |
