Chemical formula: C₁₉H₁₈FN₃O Molecular mass: 323.371 g/mol PubChem compound: 9931954
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 involves inhibition of PARP enzymatic activity and the trapping of PARP-DNA complexes resulting in increased DNA damage, apoptosis, and cell death.
Rucaparib has been shown to have in vitro and in vivo anti-tumour activity in BRCA mutant cell lines through a mechanism known as synthetic lethality, whereby the loss of two DNA repair pathways is required for cell death. Increased rucaparib-induced cytotoxicity and anti-tumour activity was observed in tumour cell lines with deficiencies in BRCA1/2 and other DNA repair genes. Rucaparib has been shown to decrease tumour growth in mouse xenograft models of human cancer with or without deficiencies in BRCA.
Plasma exposures of rucaparib, as measured by Cmax and AUC, were approximately dose proportional at evaluated doses (40 to 500 mg daily, 240 to 840 mg twice a day). Steady state was achieved after 1 week of dosing. Following repeated twice daily dosing, the accumulation based on AUC ranged from 3.5 to 6.2 fold.
In patients with cancer following rucaparib 600 mg taken twice daily, the mean steady-state Cmax was 1940 ng/mL and AUC0-12h was 16900 h⋅ng/mL with Tmax of 1.9 hours. The mean absolute oral bioavailability following a single oral dose of 12 to 120 mg rucaparib was 36%. The absolute oral bioavailability at 600 mg has not been determined. In patients with cancer following a high-fat meal, the Cmax increased by 20%, the AUC0-24h increased by 38%, and the Tmax was delayed by 2.5 hours, as compared with dosing under fasted conditions. The food effect on PK was not considered clinically significant. Rucaparib can be administered with or without food.
The in vitro protein binding of rucaparib is 70.2% in human plasma at therapeutic concentration levels. Rucaparib preferentially distributed to red blood cells with a blood-to-plasma concentration ratio of 1.83. In patients with cancer, 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, rucaparib is metabolised primarily by CYP2D6, and to a lesser extent by CYP1A2, and CYP3A4. In a population PK analysis, no clinically relevant PK differences were observed among patients with different CYP2D6 phenotypes (including poor metabolizers, n=9; intermediate metabolizers, n=71; normal metabolizers, n=76; and ultra-rapid metabolizers, n=4) or patients with different CYP1A2 phenotypes (including normal metabolizers, n=28; hyperinducers, n=136). The results should be interpreted with caution due to the limited representation of some subgroup phenotypes.
Following administration of a single oral dose of [14C]-rucaparib to patients with solid tumours, unchanged rucaparib accounted for 64.0% of the radioactivity in plasma. Oxidation, N-demethylation, N-methylation, glucuronidation, and N-formylation were the major metabolic pathways for rucaparib. The most abundant metabolite was M324, an oxidative deamination product of rucaparib, accounting for 18.6% of the radioactivity in plasma. In vitro, M324 was at least 30 fold less potent than rucaparib against PARP-1, PARP-2, and PARP-3. Other minor metabolites accounted for 13.8% of the radioactivity in plasma. Rucaparib accounted for 44.9% and 94.9% of radioactivity in urine and faeces, respectively; while M324 accounted for 50.0% and 5.1% of radioactivity in urine and faeces, respectively.
The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg. Following administration of a single oral dose of [ 14 C]-rucaparib 600 mg to patients, the overall mean recovery of radioactivity was 89.3%, with a mean recovery of 71.9% in faeces and 17.4% in urine by 288 hours post dose. Ninety percent of the observed faecal recovery was achieved within 168 hours postdose. The mean half-life (t½) of rucaparib was 25.9 hours.
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 OAPT1B1 and OATP1B3. Effect of P-gp and BCRP inhibitors on rucaparib PK cannot be ruled out.
In vitro, 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.
In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. At clinical exposures, rucaparib did not inhibit bile salt export pump (BSEP), OATP1B1, OATP1B3, OAT1 and OAT3. Inhibition of MRP4 by rucaparib cannot be fully ruled out at clinical exposures. No interaction with MRP2 or MRP3 was observed in vitro at the clinical exposure of rucaparib, however, mild bi-phasic activation and inhibition of MRP2 and concentration dependent inhibition of MRP3 were observed at concentrations higher than the observed plasma Cmax of rucaparib. The clinical relevance MRP2 and MRP3 interaction in the gut is not known. In vitro, rucaparib is an inhibitor of the BCRP and P-gp efflux transporters. Potential in vivo BCRP inhibition cannot be excluded. No significant P-gp inhibition was observed in vivo (section 4.5).
Population PK analysis suggested that concomitant use of PPIs is unlikely to have clinically meaningful impact on rucaparib PK. A firm conclusion cannot be made regarding the effect of co-administration of rucaparib and PPIs because dose level and time of administration have not been documented in detail for the PPIs.
Based on population PK analysis, no clinically significant relationships were identified between predicted steady-state exposure and patient’s age, race, and body weight. Patients included in the population PK study were aged 21 to 86 years (58% <65 years, 31% 65-74 years, and 11% >75 years), 82% were Caucasian, and had body weights between 41 and 171 kg (73% had body weight >60 kg).
No formal studies of rucaparib in patients with hepatic impairment have been conducted. A population PK analysis was performed to evaluate the effect of hepatic impairment on the clearance of rucaparib in patients receiving rucaparib 600 mg twice daily. No clinically important differences were observed between 34 patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1.0 to 1.5 times ULN and any AST) and 337 patients with normal hepatic function. Limited data are available for patients with moderate or severe hepatic impairment.
No formal studies of rucaparib in patients with renal impairment have been conducted. A population PK analysis was performed to evaluate the effect of renal impairment on the clearance of rucaparib in patients receiving rucaparib 600 mg twice daily. Patients with mild renal impairment (N=149; CLcr between 60 and 89 mL/min, as estimated by the Cockcroft-Gault method) and those with moderate renal impairment (N=76; CLcr between 30 and 59 mL/min) showed approximately 15% and 33% higher steady-state AUC, respectively, compared to patients with normal renal function (N=147; 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.
The findings in non-clinical toxicology studies performed with oral rucaparib were generally consistent with the adverse events observed in clinical studies. In repeat-dose toxicity studies of up to 3 months duration in rats and dogs, the target organs were the gastrointestinal, haematopoietic, and lymphopoietic systems. These findings occurred at exposures below those observed in patients treated at the recommended dose, and were largely reversible within 4 weeks of cessation of dosing. In vitro, the IC50 of rucaparib against the human ether-à-go-go related gene (hERG) was 22.6 μM, which is approximately 13-fold higher than the Cmax in patients at the recommended dose.
Intravenous administration of rucaparib in the rat and dog induced cardiac effects at a high Cmax (5.4 to 7.3-fold higher than patients), but not at a lower Cmax (1.3 to 3.8-fold higher than patients). No cardiac effects were observed with oral dosing of rucaparib in repeat-dose toxicology studies at a rucaparib Cmax comparable to that observed in patients. Although no cardiac effects were observed following oral dosing, based on the findings in the intravenous studies and safety margins, cardiac effects in patients cannot be excluded when rucaparib is given orally.
Carcinogenicity studies have not been performed with rucaparib.
Rucaparib was not mutagenic in a bacterial reverse mutation (Ames) assay. Rucaparib induced structural chromosomal aberrations in the in vitro human lymphocyte chromosomal aberration assay.
In an embryo-foetal development study in rats, rucaparib was associated with post-implantation loss at exposures of approximately 0.04 times the human AUC at the recommended dose.
Fertility studies have not been conducted with rucaparib. No effects on male and female fertility were observed in 3-month general toxicology studies in rats and dogs at exposures of 0.09 to 0.3 times the human AUC at the recommended dose. A potential risk cannot be ruled out based on the safety margin observed. In addition, according to its mechanism of action rucaparib may have the potential to impair fertility in humans.
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