What are the potential drug interactions with olaparib (Poly (ADP-ribose) polymerase inhibitor) in an adult cancer patient with a history of breast, ovarian, or prostate cancer and possible comorbid conditions?

Olaparib Drug Interactions

Olaparib is extensively metabolized by CYP3A4/5 enzymes, making it highly susceptible to drug-drug interactions with strong CYP3A inhibitors and inducers, which can significantly alter plasma exposure and toxicity risk. 1

Critical Drug Interactions to Avoid

Strong CYP3A Inhibitors

• Avoid concurrent use of strong CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, cobicistat) as they can dramatically increase olaparib plasma concentrations and risk of dose-limiting toxicities, particularly hematologic adverse events. 1
• If a strong CYP3A inhibitor cannot be avoided, reduce olaparib dose substantially and monitor closely for increased toxicity, especially anemia and thrombocytopenia. 1

Strong CYP3A Inducers

• Avoid concurrent use of strong CYP3A inducers (rifampin, phenytoin, carbamazepine, St. John's wort) as they can significantly reduce olaparib plasma exposure and compromise efficacy. 1
• Consider alternative medications that do not induce CYP3A when treating concurrent conditions. 1

Olaparib as a Perpetrator of Drug Interactions

Enzyme and Transporter Inhibition

• Olaparib inhibits several drug transporters and enzymes, creating a high risk for drug-drug interactions when combined with substrates of these pathways. 1
• Monitor closely when olaparib is combined with medications that are substrates of P-glycoprotein, BCRP, OATP1B1, or OCT1 transporters. 1

Specific Contraindicated Combinations

Concurrent Chemotherapy

• Do not administer olaparib concurrently with capecitabine in the adjuvant setting for triple-negative breast cancer with germline BRCA1/2 mutations due to insufficient safety data, no established clinical benefit, and overlapping hematologic toxicity. 2
• Choose one agent based on mutation status: olaparib 300 mg orally twice daily for 1 year if germline BRCA1/2 mutation present (Category 1), or capecitabine if no germline BRCA1/2 mutation. 2

Radiation Therapy Considerations

• Patients receiving skeletal radiation are at substantially elevated risk for severe hematologic toxicity when also receiving olaparib. 3
• Intensify complete blood count monitoring to at least every 2 weeks when combining olaparib with skeletal radiation therapy. 3
• Maintain type and screen availability at all times and ensure transfusion support readiness for severe anemia. 3

Food Effects and Administration

Dosing Considerations

• Olaparib demonstrates moderate-to-high interindividual variability in plasma exposure, which can affect both efficacy and toxicity. 1
• Higher olaparib exposure is directly associated with increased toxicity, predominantly hematological adverse events including anemia (39-63% any grade, 17-31% grade ≥3), thrombocytopenia (20-46% any grade, 13-29% grade ≥3), and neutropenia (23-26% any grade, 6-13% grade ≥3). 3

Monitoring Requirements for Drug Interaction Management

Mandatory Laboratory Surveillance

• Monitor complete blood counts throughout therapy, with increased frequency when drug interactions are suspected or unavoidable. 3
• Monitor hepatic and renal function regularly, as olaparib undergoes extensive hepatic metabolism and renal elimination. 3
• Assess for signs of cumulative toxicity, though long-term olaparib exposure has not shown evidence of cumulative toxicity in clinical trials. 4

Clinical Vigilance for Interaction-Related Toxicity

• Watch for exacerbation of common olaparib adverse events when interacting drugs are introduced: nausea (53-77%), fatigue/asthenia (53-63%), vomiting (22-40%), and diarrhea (34%). 3
• Monitor for rare but serious adverse effects that may be potentiated by drug interactions: myelodysplastic syndrome/acute myeloid leukemia (~2%), thromboembolic events, and drug-induced pneumonitis. 3

Special Populations Requiring Enhanced Interaction Monitoring

Patients with Organ Dysfunction

• Renal dysfunction and hepatic impairment require dose adjustments and heightened awareness of drug interaction potential, as these conditions can further alter olaparib pharmacokinetics. 1
• The combination of organ dysfunction with interacting medications creates compounded risk for toxicity. 1

Polypharmacy in Cancer Patients

• Cancer patients frequently require multiple concurrent medications for comorbid conditions (anticoagulants, antihypertensives, diabetes medications, pain management), necessitating comprehensive medication reconciliation before initiating olaparib. 1
• Review all prescription medications, over-the-counter drugs, and herbal supplements for potential CYP3A interactions before each treatment cycle. 1