rucaparib

Action and Spectrum

Actions and Spectrum: 

Actions: 

• Inhibition of PARP enzymes: rucaparib inhibits PARP enzymes involved in DNA repair. It leads to the accumulation of DNA damage in cancer cells, ultimately resulting in cell death. 
• Synthetic lethality: rucaparib takes advantage of synthetic lethality, which occurs when a cancer cell has a genetic mutation that impairs its ability to repair DNA and is then treated with a drug that further inhibits DNA repair. This combination leads to cancer cell death while sparing normal cells. 

Spectrum: 

• Ovarian cancer: rucaparib is indicated for the maintenance treatment of recurrent ovarian cancer that has responded to platinum-based chemotherapy in patients with a germline or somatic BRCA mutation. 
• Pancreatic cancer: rucaparib is being investigated as a potential treatment for pancreatic cancer with BRCA mutations. 
• Other types of cancer: rucaparib is being investigated for its potential to treat other types of cancer with BRCA mutations, including breast cancer and prostate cancer. 

Drug Interaction

Adverse Reaction

Frequency defined:  

>10% 

Increased creatinine  

Decreased hemoglobin  

Increased cholesterol  

Nausea  

Fatigue/asthenia  

Increased ALT  

Increased AST  

Abdominal pain/distention  

Decreased platelets  

Decreased leukocytes  

Rash  

Dysgeusia  

Anemia  

AST/ALT elevation  

Decreased neutrophils  

Constipation  

Vomiting  

Increased alkaline phosphatase  

Diarrhea  

Thrombocytopenia  

Decreased lymphocytes  

Nasopharyngitis  

Stomatitis  

Decreased appetite  

Neutropenia  

Dizziness  

Dyspepsia  

Headache  

Dyspnea  

Insomnia  

Pyrexia  

Peripheral edema  

Depression  

1-10% 

Neutropenia  

Fatigue  

Increased ALT  

Decreased neutrophils  

Decreased lymphocytes  

Thrombocytopenia  

Nausea  

Vomiting  

Increased cholesterol  

Abdominal pain/distention  

Decreased leukocytes  

Decreased platelets 

Constipation  

Stomatitis  

Rash  

Decreased appetite  

Increased AST   

<1% 

Diarrhea 

Upper respiratory tract infection 

Dyspnea 

Dysgeusia 

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

• Hypersensitivity: rucaparib is contraindicated in patients with known hypersensitivity to any of its components. 
• Pregnancy: rucaparib can cause fetal harm when administered to a pregnant woman. It is contraindicated in pregnancy, and women of reproductive potential should be advised to use effective contraception during treatment and for six months after the last dose. 
• Breastfeeding: It is unknown if rucaparib is excreted in human milk, and the effects on a nursing infant are unknown. Breastfeeding should be avoided during treatment with rucaparib and for two weeks after the last dose. 
• Hepatic impairment: rucaparib is metabolized by the liver, and patients with moderate or severe hepatic impairment may have increased exposure to the drug. Caution should be used when administering rucaparib to patients with hepatic impairment. 
• Renal impairment: rucaparib is eliminated through the kidneys, and patients with severe renal impairment may have increased exposure to the drug. Caution should be used when administering rucaparib to patients with renal impairment. 
• Myelodysplastic syndrome and acute myeloid leukemia: Treatment with rucaparib have been associated with development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Patients should be monitored for signs and symptoms of MDS and AML during treatment with rucaparib and for at least six months after the last dose. 

Pregnancy / Lactation

Pregnancy consideration: The drug is toxic and unsafe for pregnant women and the developing fetus.  

Breastfeeding warnings: No data on the excretion of rucaparib in breast milk is available. Because of possible serious effects, women are advised to breastfeed two weeks after the last dose of rucaparib. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no affirmation of risk to the fetus found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a product in humans; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits. The drug is not for pregnant women. 
• Category N: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

rucaparib is a drug that belongs to the class of PARP inhibitors. PARP stands for poly (ADP-ribose) polymerase, an enzyme in DNA repair. rucaparib inhibits PARP, leading to an accumulation of DNA damage and ultimately causing cancer cells to die. 

rucaparib is primarily used to treat ovarian cancer, particularly in patients with BRCA mutations. It has also shown promise in the treatment of other types of cancer, including prostate, breast, and pancreatic cancer 

Pharmacodynamics: 

The pharmacodynamics of rucaparib is related to its mechanism of action as a PARP inhibitor. PARP inhibitors like rucaparib block the activity of PARP enzymes involved in DNA repair processes. Specifically, PARP inhibitors prevent PARP enzymes from repairing single-strand DNA breaks, leading to an accumulation of DNA damage and, ultimately, cell death. 

rucaparib selectively binds to and inhibits the catalytic activity of PARP1, PARP2, and PARP3 enzymes. By inhibiting these enzymes, rucaparib can induce synthetic lethality in cancer cells with homologous recombination (HR) DNA repair deficiencies, such as those with BRCA mutations.

HR-deficient cells rely on PARP enzymes to repair DNA damage, and when PARP is inhibited by rucaparib, these cells cannot repair the damage and ultimately die. Normal cells with functional HR repair pathways are less affected by PARP inhibition and can continue to repair DNA damage using alternative pathways. 

rucaparib’s selectivity for PARP1, PARP2, and PARP3 is essential because it can minimize off-target effects and toxicity. Additionally, rucaparib has been shown to increase the sensitivity of cancer cells to radiation and chemotherapy, potentially leading to improved treatment outcomes. 

Pharmacokinetics: 

Absorption 

The absolute bioavailability is 36% (ranging between 30-45%) 

The peak plasma concentration is achieved in 1.9 hours 

The peak plasma concentration at steady-state is 1940 ng/mL 

The area under the curve is 16,900 hr⋅ng/mL 

Distribution 

The volume of distribution is 113-262 L 

The protein-bound is 70% 

Metabolism 

The drug is metabolized (in vitro) primarily by CYP2D6 and secondarily by CYP3A4 and CYP1A2  

Elimination and Excretion 

The half-life of the drug is 17-19 hours 

The rate of clearance is 15.30-79.2 L/hr 

Adminstartion

Administration: 

rucaparib is available in tablet form for oral administration. It should be taken with or without food, preferably at the same time every day. The recommended starting dose of rucaparib for treating ovarian cancer is 600 mg, taken orally twice daily, for a total daily dose of 1200 mg. The dose may be adjusted based on individual patient factors, such as tolerability and response to treatment. 

If a dose of rucaparib is missed, it should be taken as soon as possible unless it is close to the next scheduled dose. In that case, the missed dose should be skipped, and the regular dosing schedule should be resumed. Patients should not take double doses of rucaparib to make up for a missed dose. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: rucaparib (Rx) 

Pronounced: roo kap’ a rib 

Why do we use rucaparib? 

rucaparib is primarily used for the treatment of ovarian cancer. It is a type of PARP inhibitor that blocks the activity of PARP enzymes involved in DNA repair. It leads to an accumulation of DNA damage in cancer cells, ultimately causing them to die. 

rucaparib is specifically indicated for the maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that has responded to platinum-based chemotherapy. It is used in patients who have a germline or somatic BRCA mutation and who have completed at least two prior rounds of platinum-based chemotherapy. 

rucaparib has also shown promise in treating other types of cancer, including prostate, breast, and pancreatic cancer. It may be combined with other cancer treatments like chemotherapy or radiation therapy to improve treatment outcomes.