Drug Interaction Report

MONITOR: Coadministration with pretomanid may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP1B3), and/or P-glycoprotein (P-gp). The proposed mechanism, based on in vitro data, is decreased clearance due to pretomanid-mediated inhibition of BCRP, OATP1B3, and/or P-gp. The clinical significance is unknown as data are limited and conflicting.

MANAGEMENT: Until more information is available, the manufacturers of pretomanid recommend that clinicians should be aware of the potential for enhanced pharmacologic effects with drugs that are substrates of BCRP, OATP1B3, and/or Pg-p, particularly those with a narrow therapeutic range, when pretomanid is coadministered. Dosage adjustments as well as clinical and laboratory monitoring of the BCRP, OATP1B3, and/or P-gp substrate drug should be considered whenever pretomanid is added to or withdrawn from therapy with these drugs. Patients should be monitored for the development of adverse effects.

GENERALLY AVOID: Coadministration of imatinib with strong CYP450 3A4 inhibitors such as grapefruit juice, may significantly increase the plasma concentrations of imatinib, a known substrate of CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of imatinib by certain compounds present in grapefruits. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. In a single-dose study, coadministration of imatinib with ketoconazole (a strong CYP450 3A4 inhibitor) increased imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) by 26% and 40%, respectively.

MANAGEMENT: Patients treated with imatinib should preferably avoid the consumption of grapefruit or grapefruit juice. If coadministration is unavoidable, monitor for prolonged and/or increased pharmacologic effects of imatinib, including edema, hematologic toxicity and immunosuppression.

GENERALLY AVOID: Coadministration with alcohol may increase the risk of hepatotoxicity associated with the use of combination drug regimens that include pretomanid.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of pretomanid. The mechanism has not been reported. Compared with the fasted state, oral administration of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) increased mean systemic exposure (AUC) and peak plasma concentration (Cmax) of pretomanid by 88% and 76%, respectively.

MANAGEMENT: Patients should avoid alcohol use during treatment with pretomanid. In addition, to ensure maximal oral absorption, pretomanid should be administered with food. Tablets should be swallowed whole.