Rucaparib

Rucaparib Uses, Dosage, Side Effects, Food Interaction and all others data.

Rucaparib is a potent mammalian poly(ADP-ribose) polymerase (PARP) 1, 2 and 3 inhibitor with anticancer properties. PPAR is an enzyme that plays an essential role in DNA repair by activating response pathways and facilitating repair , and defects in these repair mechanisms have been demonstrated in various malignancies, including cancer. Regulation of repair pathways is critical in promoting necessary cell death. BRCA genes are tumor suppressor genes mediate several cellular process including DNA replication, transcription regulation, cell cycle checkpoints, apoptosis, chromatin structuring and homologous recombination (HR). Homologous recombination deficiency (HRD), along with PPAR inhibition, is a vulnerability that enhances the cell death pathway when the single mutations alone would permit viability. Ovarian cancer commonly possesses defects in DNA repair pathways such as HRD due to BRCA mutations or otherwise.

There are three main types of ovarian cancer: epithelial (90%), germ cell (5%) and sex cord stromal cell (5%). Epithelial ovarian, being the most common, fifth leading cause of cancer-related deaths in women in the United States. Advanced ovarian cancer particularly poses challenges due to reduced therapeutic response rates from standard platinum-based chemotherapy and overall survival rates. Rucaparib has shown to induce cytotoxicity in tumor cell lines with deficiencies in BRCA1/2 and other DNA repair genes . Of all the BRCA1/2 mutations in ovarian cancer, most are due to germline mutations (18%), and approximately 7% represent somatic mutations acquired within the tumor .

The indication of rucaparib as an oral monotherapy in patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer was granted accelerated approval in 2016 for selected patients who have previously received greater than two lines of platinum-based therapy. It is currently marketed in the US under the brand name Rubraca that contains rucaparib camsylate as the active ingredient. The identification of patients who are eligible for rucaparib therapy is performed via in vitro diagnostic tests to detect the presence of a deleterious BRCA mutation (germline and/or somatic). The FDA-approved test qualitatively detects sequence alterations in BRCA1 and BRCA2 (BRCA1/2) genes. More information can be found on the FDA Website .

Rucaparib
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Rucaparib
Availability	Prescription only
Generic	Rucaparib
Rucaparib Other Names	Rucaparib
Related Drugs	estradiol, Premarin, carboplatin, doxorubicin, cisplatin, paclitaxel, Avastin, Xtandi, Casodex, Zytiga
Weight	200mg, 250mg, 300mg
Type	Oral tablet
Formula	C₁₉H₁₈FN₃O
Weight	Average: 323.371 Monoisotopic: 323.143390375
Protein binding	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 .
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Rucaparib is an anti-cancer agent used to treat recurrent ovarian, fallopian tube, or peritoneal cancer.

Indicated as monotherapy for the treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for rucaparib.

Rucaparib is also used to associated treatment for these conditions: Advanced Ovarian Cancer

How Rucaparib works

Poly (ADP-ribose) polymerase (PARP) enzymes play a role in DNA repair. PPAR-1 is responsible in repairing single stranded breaks (SSBs) in base excision repair (BER). PARP1 also functions in nonhomologous end-joining (NHEJ) regulation, chromatin remodeling and homologous recombination (HR) DNA repair pathways . When PARP is inhibited, single-strand breaks become double-strand breaks, which are typically repaired via homologous recombination . Pre-existing homologous recombination deficiency (HRD) may occur through mutations in the BRCA1 or BRCA2 genes, which confers persistant cell repair and growth in cancer cells.

Rucaparib is an inhibitor of PARP-1, PARP-2, and PARP-3. Via an inhibitory effect on the PARP enzymatic activity, rucaparib decreases the formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death . It is proposed that PARP inhibition specifically targets tumor cells with preexisting HRD, such as those cells possessing mutations in the BRCA1 or BRCA2 genes . Rucaparib induces synthetic lethality by disrupting ingle- and double-strand repair pathways leading to tumor cell death. It is also suggested that PARP inhibition can lead to trapping of PARP-1 enzyme on damaged DNA, effectively preventing continuation of the DNA repair process; defective BRCA1 recruitment to damaged DNA; and activation of alternative DNA repair such as error-prone nonhomologous end joining (NHEJ) or alternative end joining pathways leading to mutations or chromosomal changes and ultimately cell death .

Toxicity

According to a bacterial reverse mutation (Ames) test, rucaparib has shown to be mutagenic. It was also clastogenic in an in vitro chromosomal aberration assay in cultured human lymphocytes. Rucaparib has a genotoxic potential. Based on its mechanism of action and findings from animal studies, rucaparib can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of rucaparib .

Food Interaction

Exercise caution with grapefruit products. Rucaparib is primarily metabolized through CYP2D6 but is also metabolized by CYP3A4 and CYP1A2. Grapefruit inhibits CYP3A4 metabolism, which may increase rucaparib serum levels.
Exercise caution with St. John's Wort. Rucaparib is primarily metabolized through CYP2D6 but is also metabolized by CYP3A4 and CYP1A2. St. John's Wort induces CYP3A4 metabolism, which may reduce rucaparib serum levels.
Take with or without food. High-fat meals may increase the bioavailability and delay the Tmax of rucaparib.

Rucaparib Drug Interaction

Moderate: degarelix, denosumabUnknown: multivitamin with minerals, omega-3 polyunsaturated fatty acids, multivitamin with minerals, ergocalciferol

Rucaparib Disease Interaction

Moderate: hepatic impairment, MDS/AML, renal impairment

Volume of Distribution

Following a single intravenous dose of 12mg to 40mg rucaparib, the steady-state volume of distribution was 113L to 262L .

Elimination Route

Rucaparib demonstrates a linear pharmacokinetic properties 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. The time to reach the steady-state peak plasma concentration (Tmax) was 1.9 hours at the 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 AUC 0-24h was increased by 38%, and T max was delayed by 2.5 hours, as compared to dosing under fasted conditions .

Half Life

Following a single oral dose of 600mg rucaparib, the mean terminal half life (t1/2) was 17-19 hours .

Clearance

Following continuous 600mg rucaparib administration orally twice daily, the apparent clearance ranges from 15.3 to 79.2 L/hour. The clearance ranged from 13.9 to 18.4 L/hour, following a single intravenous dose of rucaparib 12 mg to 40 mg .