Drug Interaction Report

GENERALLY AVOID: Coadministration with potent and moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of olaparib, which is primarily metabolized by the isoenzyme. In a drug interaction study with 22 patients, mean olaparib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 71% and 87%, respectively, during coadministration with the potent CYP450 3A4 inducer rifampin. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that a moderate inducer (efavirenz) may decrease olaparib Cmax by 20% to 30% and AUC by 50% to 60%.

MANAGEMENT: Concomitant use of olaparib with potent and moderate CYP450 3A4 inducers should generally be avoided. If coadministration is required, the potential for decreased efficacy of olaparib should be considered.

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of olaparib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. In a drug interaction study with 57 patients, mean olaparib systemic exposure (AUC) was increased approximately 2.7-fold by the potent CYP450 3A4 inhibitor itraconazole. Simulations using physiologically-based pharmacokinetic (PBPK) models suggest that a moderate inhibitor (fluconazole) may increase the AUC of olaparib by 2.2-fold. The interaction has not been studied with grapefruit juice. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to olaparib may increase the risk of adverse effects such as hematologic toxicity, nausea, vomiting, diarrhea, anorexia, dyspepsia, and abdominal pain or discomfort.

MANAGEMENT: Food containing grapefruit, grapefruit juice, Seville orange (a citrus relative of the grapefruit), or Seville orange juice should be avoided during treatment with olaparib. Some authorities also recommend avoiding starfruit (carambola) and pomegranate.