Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of rucaparib has not fully been characterized.

Cardiac Electrophysiology

A positive concentration-QTc relationship was observedin patients who were administered continuous dosages 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 (90% confidence interval [CI]) QTcF increase from baseline at steady state of Rubraca 600 mgtwice daily was 14.9 msec (11.1, 18.7 msec).

Pharmacokinetic Properties

12.3 Pharmacokinetics

The AUC and Cmax of rucaparib demonstrated linear pharmacokinetics over a dose range from 240 mg to 840 mg twice daily (0.4 times to 1.4 times the approved recommended dosage). The mean (coefficient of variation [CV]) steady-state rucaparib Cmax is 1,940 ng/mL (54%) and AUC0-12h is 16,900 h⋅ng/mL (54%) at the approved recommended dosage. The mean AUC accumulation ratio is 3.5 to 6.2 fold.

Absorption

The median Tmax (min, max) at the steady state is 1.9 hours (0, 5.98) at the approved recommended dosage. The mean (min, max) absolute bioavailability is 36% (30%, 45%).

Effect of Food

Following a high-fat meal (approximately 800-1000 calories, including approximately 250 calories from carbohydrates, approximately 500-600 calories from fat, approximately 150 calories from protein), the Cmax was increased by 20%, AUC0-24h was increased by 38%, and the Tmax was delayed by 2.5 hours, as compared to fasted conditions [see Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution is 2300 L (21%).
Rucaparib is 70% bound to human plasma proteins in vitro. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.8.

Elimination

The mean apparent total clearance at steady state is 44.2 L/h (45%) and the mean terminal elimination half-life is 26 (39%) hours.

Metabolism
In vitro, rucaparib is primarily metabolized by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. In addition to CYP-based oxidation, rucaparib also undergoes N-demethylation, N-methylation, and glucuronidation.

Excretion

Following a single oral dose of radiolabeled rucaparib, unchanged rucaparib accounted for 64% of the radioactivity.
Rucaparib accounted for 45% and 95% of radioactivity in urine and feces, respectively.
Specific Populations

Age (20 to 86 years), race (White, Black and Asian), sex, body weight (41 to 171 kg), mild to moderate renal impairment (CLcr ≥ 30 mL/min), mild hepatic impairment (total bilirubin < ULN and AST > ULN or total bilirubin 1 to 1.5 x ULN and any AST), and CYP2D6 or CYP1A2 genotype polymorphisms did not have a clinically meaningful effect on the pharmacokinetics of rucaparib. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or severe hepatic impairment (total bilirubin > 3 x ULN and any AST) has not been studied.Hepatic Impairment

Moderate hepatic impairment (total bilirubin > 1.5 to 3 x ULN and any AST) increased rucaparib AUC by 45%, but had no effect on Cmax compared to patients with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Effect of Other Drugs on Rucaparib
Concomitant administration of Rubraca with a proton pump inhibitor had no clinically meaningful effect on steady-state concentrations of rucaparib.

Effect of Rucaparib on Other Drugs
Concomitant administration of Rubraca with rosuvastatin (BCRP substrate) had no clinically meaningful effect on the concentrations of rosuvastatin.
Coadministration of Rubraca with the following substrates increased the Cmax of each coadministered substrate by ≤ 1.1- fold and increased the AUC of each substrate as follows:
•   Caffeine (CYP1A2): by 2.6-fold
•   Midazolam (CYP3A4): by 1.4-fold
•   Warfarin (CYP2C9): by 1.5-fold
•   Omeprazole (CYP2C19): by 1.6-fold
•   Digoxin (P-glycoprotein): by 1.2-fold 
Concomitant administration of Rubraca with an oral contraceptive containing ethinylestradiol and levonorgestrel (CYP3A substrates): increased ethinylestradiol AUC by 1.4-fold and levonorgestrel AUC by 1.6-fold, but did not have a clinically meaningful effect on their Cmax.


In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Rucaparib inhibited CYP2C8, CYP2D6 and induced CYP1A2.
UDP-glucuronosyltransferase (UGT) Enzymes: Rucaparib inhibited UGT1A1.
Transporter Systems: Rucaparib is a substrate of P-gp and BCRP Rucaparib is not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
Rucaparib inhibited OATP1B1, OATP1B3, OAT1, OAT3, MATE1, MATE2-K, OCT1, OCT2, and MRP4. Rucaparib did not inhibit MRP2, MRP3, or BSEP.