Usage
Olaparib is a targeted therapy drug prescribed for specific types of cancers, including:
- Ovarian Cancer: Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer responsive to platinum-based chemotherapy. Treatment of advanced ovarian cancer with germline BRCA mutations.
- Breast Cancer: Treatment of germline BRCA-mutated, HER2-negative metastatic or early breast cancer, particularly in those who have received prior chemotherapy or are unsuitable for endocrine therapy.
- Pancreatic Cancer: Treatment of metastatic pancreatic cancer with germline BRCA mutations in combination with other chemotherapy
- Prostate Cancer: Treatment of metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene mutations including BRCA1/2, often in combination with Abiraterone.
Pharmacological Classification: PARP (Poly ADP-ribose polymerase) inhibitor.
Mechanism of Action: Olaparib inhibits PARP enzymes involved in DNA repair. Cancer cells with BRCA mutations or other defects in homologous recombination repair (HRR) pathways rely on PARP for DNA repair. By inhibiting PARP, Olaparib prevents DNA repair, leading to cell death in these cancer cells, while sparing normal cells with intact HRR pathways. This is known as synthetic lethality.
Alternate Names
Generic Name: Olaparib
Brand Names: Lynparza
How It Works
Pharmacodynamics: Olaparib selectively targets PARP enzymes, crucial for single-strand DNA break repair. Its primary anti-cancer effect stems from exploiting the concept of “synthetic lethality” in cancer cells deficient in homologous recombination repair. Inhibition of PARP in these cells leads to accumulation of single-strand breaks that convert into double-strand breaks, resulting in genomic instability and ultimately apoptosis (programmed cell death).
Pharmacokinetics:
- Absorption: Olaparib is well-absorbed orally. Food can increase exposure in capsule form.
- Metabolism: Primarily metabolized by CYP3A4, making it susceptible to drug interactions with CYP3A4 inducers or inhibitors.
- Elimination: Excreted via both renal and hepatic pathways.
Mode of Action: Olaparib binds to and inhibits PARP enzymes, specifically PARP1 and PARP2, which are involved in the base excision repair pathway. This pathway is essential for repairing single-strand DNA breaks. By inhibiting PARP, olaparib traps it on the DNA, preventing the repair process. The trapped PARP-DNA complexes stall replication forks and cause double-strand DNA breaks, leading to cell death, especially in cancer cells with deficient homologous recombination DNA repair mechanisms.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Olaparib acts through direct enzyme inhibition of PARP. It doesn’t bind to receptors or directly modulate neurotransmitters.
Elimination Pathways: Olaparib is eliminated through a combination of hepatic metabolism (mainly via CYP3A4) and renal excretion.
Dosage
Standard Dosage
Adults:
- Tablets: 300 mg (two 150 mg tablets) twice daily (total 600 mg daily), with or without food.
- Capsules: 400mg BD PO. The dose should be taken two hours before food or one hour after food.
- In Combination with Abiraterone: 300mg BD PO.
Treatment should be continued until disease progression or unacceptable toxicity.
Children:
Safety and efficacy haven’t been fully established in pediatric patients. A phase 1 study suggested a dose of 187.5 mg/m2 twice daily, but more research is needed.
Special Cases:
- Elderly Patients: No initial dose adjustment is required, but close monitoring is advised. Limited data exists for patients 75 years and older.
- Patients with Renal Impairment:
- Mild (CrCl 51-80 mL/min): No dose adjustment needed.
- Moderate (CrCl 31-50 mL/min): Reduce dose to 200 mg twice daily.
- Severe (CrCl ≤30 mL/min): Not recommended.
- Patients with Hepatic Dysfunction:
- Mild to Moderate (Child-Pugh A or B): No dose adjustment needed, but careful monitoring is required.
- Severe (Child-Pugh C): Not recommended.
- Patients with Comorbid Conditions: Careful monitoring is necessary for patients with pre-existing medical conditions, especially pulmonary or hematologic issues.
Clinical Use Cases
Olaparib dosing is based on cancer type and patient-specific factors, not specific clinical settings like intubation or surgery. The dosages mentioned above under “Standard Dosage” apply to the relevant cancer indications.
Dosage Adjustments
Dose modifications may be necessary based on individual patient factors:
- Hematologic Toxicity: Dose interruptions or reductions may be required for severe anemia, neutropenia, or thrombocytopenia.
- Pneumonitis: Discontinue Olaparib if pneumonitis is confirmed.
- Hepatotoxicity: Discontinue Olaparib if severe drug-induced liver injury occurs.
- Drug Interactions: Adjust dose based on co-administration with CYP3A4 inhibitors or inducers.
Side Effects
Common Side Effects:
- Nausea, vomiting, diarrhea
- Fatigue, weakness
- Headache
- Decreased appetite, changes in taste
- Abdominal pain or discomfort
- Musculoskeletal pain
- Cough, shortness of breath
- Anemia, thrombocytopenia, neutropenia (low blood cell counts)
- Rash
Rare but Serious Side Effects:
- Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML): Can be fatal.
- Pneumonitis: Can be fatal, particularly in patients with lung conditions or prior lung treatment.
- Allergic reactions
Long-Term Effects:
- Increased risk of secondary malignancies (e.g., MDS/AML).
- Chronic fatigue.
Adverse Drug Reactions (ADR):
- MDS/AML
- Severe Hematologic toxicity
- Pneumonitis
- Allergic reactions requiring immediate intervention
Contraindications
- Hypersensitivity to olaparib.
- Breastfeeding.
Drug Interactions
- CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): Increase Olaparib levels. Dose reduction is necessary.
- CYP3A4 Inducers (e.g., rifampin, phenytoin, carbamazepine): Decrease Olaparib levels. Avoid concomitant use.
- Other Myelosuppressive Agents (e.g., chemotherapy): Increased risk of myelosuppression.
- Grapefruit or Seville oranges: Increase Olaparib exposure. Avoid consumption.
Pregnancy and Breastfeeding
- Pregnancy: Olaparib is contraindicated during pregnancy. It can cause fetal harm and pregnancy loss. Effective contraception is mandatory during treatment and for 6 months (females) or 3 months (males) after the last dose.
- Breastfeeding: Olaparib is contraindicated during breastfeeding and for 1 month after the last dose. It is unknown if olaparib is excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: PARP inhibitor; induces synthetic lethality in cancer cells with HRR deficiencies.
- Side Effects: Nausea, vomiting, fatigue, anemia, MDS/AML, pneumonitis.
- Contraindications: Pregnancy, breastfeeding, hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors/inducers, myelosuppressive agents.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 300 mg twice daily (tablets), adjust for renal impairment and drug interactions.
- Monitoring Parameters: Complete blood count (CBC), renal function, liver function, respiratory symptoms.
Popular Combinations
- Olaparib + Bevacizumab (for ovarian cancer)
- Olaparib + Abiraterone (for prostate cancer)
Precautions
- General Precautions: Assess for pre-existing hematologic, hepatic, renal, and pulmonary conditions.
- Pregnant Women: Contraindicated; effective contraception essential.
- Breastfeeding Mothers: Contraindicated.
- Children & Elderly: Limited data; careful monitoring required.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Olaparib?
A: For adults, the standard dose is 300 mg (two 150 mg tablets) twice daily. Dose adjustments are required for moderate renal impairment (200 mg twice daily) and concomitant use of CYP3A4 inhibitors.
Q2: How does Olaparib work against cancer?
A: Olaparib inhibits PARP, leading to DNA damage accumulation and cell death specifically in cancer cells with HRR pathway defects.
Q3: What are the most common side effects of Olaparib?
A: Common side effects include nausea, vomiting, fatigue, anemia, and gastrointestinal issues.
Q4: What are the serious side effects I should be aware of with Olaparib?
A: Serious side effects include MDS/AML, pneumonitis, and severe hematologic toxicities.
Q5: Can Olaparib be used during pregnancy or breastfeeding?
A: No, Olaparib is contraindicated in both pregnancy and breastfeeding due to potential risks to the fetus or infant.
Q6: Are there any specific drug interactions with Olaparib?
A: Yes, Olaparib interacts with CYP3A4 inhibitors and inducers. Dose adjustments may be necessary. Avoid grapefruit and similar fruits.
Q7: How should I monitor patients on Olaparib?
A: Monitor regularly for hematologic toxicity (CBC), renal and hepatic function, and signs of pneumonitis or other adverse effects.
Q8: What should patients avoid while taking Olaparib?
A: Patients should avoid grapefruit and similar fruits, as they can increase Olaparib levels. They should also avoid strong CYP3A4 inducers. Effective contraception is crucial during and after treatment.
Q9: What are the key patient counseling points for Olaparib?
A: Counsel patients on potential side effects, drug interactions, the importance of contraception, and the need for regular monitoring.
Q10: Can Olaparib be used in patients with severe hepatic or renal impairment?
A: Olaparib is not recommended for patients with severe hepatic impairment (Child-Pugh C) or severe renal impairment (CrCl ≤ 30 mL/min).
