Drug Interactions between rilpivirine and taletrectinib

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of taletrectinib. The proposed mechanism for the interaction is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice but has been reported for other CYP450 3A4 inhibitors. In a clinical study, taletrectinib peak plasma concentration (Cmax) increased by 1.8-fold and systemic exposure (AUC) increased by 3.3-fold following concomitant administration of itraconazole, a potent CYP450 3A inhibitor. According to the product labeling, administration of taletrectinib with a moderate CYP450 3A inhibitor is predicted to increase taletrectinib Cmax and AUC by up to 1.5- and 2.6-fold, respectively. Increased exposure to taletrectinib may increase the risk and/or severity of adverse effects such as hepatotoxicity with liver enzyme elevations, lung toxicities, QT prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, and skeletal fractures.

ADJUST DOSING INTERVAL: Coadministration with high-fat food (1000 calories, 50% fat) increased taletrectinib Cmax and AUC by 1.5-fold, and the predicted increase in the QTc interval is 20.5 msec.

MANAGEMENT: The manufacturer recommends avoiding food or drink containing grapefruit during treatment with taletrectinib. In addition, taletrectinib should be administered on an empty stomach at about the same time each day, at least 2 hours before or 2 hours after food intake.

GENERALLY AVOID: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rilpivirine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. In 15 study subjects given rilpivirine (150 mg once daily) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily), mean rilpivirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were increased by 30%, 49% and 76%, respectively. In 16 study subjects given a single 500 mg dose of a less potent CYP450 3A4 inhibitor chlorzoxazone two hours after rilpivirine (150 mg once daily), mean rilpivirine Cmax, AUC, and Cmin were increased by 17%, 25%, and 18%, respectively. 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.

ADJUST DOSING INTERVAL: The administration of rilpivirine in a fasting state may decrease its oral absorption. Under fasted conditions, the systemic exposure to rilpivirine was 40% lower compared to normal or high-fat caloric meals (533 to 928 Kcal). The systemic exposure was 50% lower when rilpivirine was taken with a protein-rich nutritional beverage.

MANAGEMENT: Coadministration of grapefruit or grapefruit juice with rilpivirine should preferably be avoided. For optimal absorption, it is recommended to take rilpivirine on a regular schedule with a meal.