Dolutegravir/rilpivirine and Alcohol/Food Interactions

ADJUST DOSING INTERVAL: Coadministration with medications containing polyvalent cations such as aluminum, calcium, iron, or magnesium may decrease the oral bioavailability of dolutegravir. The mechanism of interaction likely involves chelation of dolutegravir by the polyvalent cation in the gastrointestinal tract. In 16 study subjects, administration of a single 50 mg dose of dolutegravir simultaneously with an antacid containing magnesium and aluminum decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 72%, 74% and 74%, respectively, compared to administration without the antacid. When the antacid was administered 2 hours after dolutegravir, the Cmax, AUC and Cmin of dolutegravir decreased by just 18%, 26% and 30%, respectively. Administration of single-dose dolutegravir simultaneously with a multivitamin decreased the Cmax, AUC and Cmin of dolutegravir by 35%, 33% and 32%, respectively. Coadministration of dolutegravir with calcium carbonate or ferrous fumarate under fed conditions counteracted the interaction and provided plasma exposures comparable to dolutegravir alone under fasted conditions.

MANAGEMENT: Dolutegravir should be administered 2 hours before or 6 hours after medications containing polyvalent cations such as antacids, laxatives, or mineral supplements. When taken with food, dolutegravir and supplements or multivitamins containing calcium or iron can be taken at the same time.

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.

Food increases the extent of absorption and slows the rate of absorption of dolutegravir. When administered with a low-, moderate- or high-fat meal, dolutegravir peak plasma concentration (Cmax) increased by 46%, 52% and 67%, systemic exposure (AUC) increased by 33%, 41% and 66%, and time to reach Cmax (Tmax) increased from 2 hours to 3, 4 and 5 hours, respectively, compared to administration under fasted conditions. Dolutegravir may be taken with or without food.