Summary

Rifampin significantly reduces olaparib plasma concentrations through strong CYP3A4 enzyme induction, potentially compromising the anticancer efficacy of olaparib. This interaction is considered clinically significant and requires careful management or alternative therapy selection.

Introduction

Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor used primarily for treating BRCA-mutated ovarian, breast, pancreatic, and prostate cancers. It works by blocking DNA repair mechanisms in cancer cells with defective homologous recombination. Rifampin is a potent antibiotic belonging to the rifamycin class, commonly used to treat tuberculosis, atypical mycobacterial infections, and as prophylaxis for meningococcal disease. Rifampin is also a strong inducer of cytochrome P450 enzymes, particularly CYP3A4, which can significantly affect the metabolism of co-administered medications.

Mechanism of Interaction

The interaction between olaparib and rifampin occurs through rifampin's potent induction of CYP3A4 enzymes in the liver and intestines. Olaparib is primarily metabolized by CYP3A4, and when rifampin induces these enzymes, it dramatically increases the clearance of olaparib from the body. Clinical studies have shown that rifampin can reduce olaparib area under the curve (AUC) by approximately 87% and maximum plasma concentration (Cmax) by about 71%. This substantial reduction in olaparib exposure occurs because rifampin increases the expression and activity of CYP3A4 enzymes, leading to enhanced first-pass metabolism and systemic clearance of olaparib.

Risks and Symptoms

The primary clinical risk of this interaction is the significant reduction in olaparib therapeutic efficacy due to subtherapeutic plasma concentrations. With an 87% reduction in olaparib exposure, patients may not achieve the necessary drug levels required for optimal PARP inhibition and anticancer activity. This could lead to treatment failure, disease progression, and compromised patient outcomes. The interaction is particularly concerning because both the extent of the reduction and the critical nature of maintaining adequate olaparib levels for cancer treatment make this a high-priority drug interaction. Additionally, the interaction persists for several weeks after rifampin discontinuation due to the time required for enzyme levels to return to baseline.

Management and Precautions

Olaparib interactions with food and lifestyle

Olaparib should be taken with food to improve absorption and reduce gastrointestinal side effects. Patients should avoid grapefruit and grapefruit juice while taking olaparib, as grapefruit can increase olaparib blood levels and potentially increase the risk of side effects. Alcohol consumption should be limited or avoided, as both olaparib and alcohol can cause fatigue and dizziness, potentially increasing these effects when used together.

Rifampin interactions with food and lifestyle

Rifampin should be taken on an empty stomach, at least 1 hour before or 2 hours after meals, as food can significantly reduce its absorption and effectiveness. Alcohol consumption should be avoided or limited while taking rifampin, as both rifampin and alcohol can cause liver toxicity, and the combination may increase the risk of hepatotoxicity. Patients should be counseled to take rifampin consistently either with or without food (preferably without) to maintain consistent blood levels.