Drug Interaction Report

ADJUST DOSE: Coadministration with potent inducers of UGT1A3 and CYP450 3A4 isoenzymes such as tipranavir/ritonavir may significantly decrease the plasma concentrations of dolutegravir, which is primarily metabolized by UGT1A1 with some contribution from CYP450 3A4. Dolutegravir is also a substrate of UGT1A3, UGT1A9, and P-glycoprotein in vitro. In 14 study subjects, administration of dolutegravir 50 mg once daily with tipranavir/ritonavir 500 mg/200 mg twice daily decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours postdose) by 46%, 59% and 76%, respectively, compared to administration without tipranavir/ritonavir.

MANAGEMENT: When prescribed in combination with tipranavir/ritonavir, the dosage of dolutegravir should be increased to 50 mg twice daily for both adults and pediatric patients 12 years of age and older who weigh at least 40 kg. The safety and efficacy of dosages above 50 mg twice daily have not been evaluated. Concomitant use of tipranavir/ritonavir with the fixed-dose combination product containing dolutegravir/lamivudine is not recommended. For concomitant use of tipranavir/ritonavir with the fixed-dose combination product containing abacavir/dolutegravir/lamivudine, it is recommended to administer an additional dose of dolutegravir 50 mg/day, separated from the combination product by 12 hours. Alternative treatment combinations that do not include metabolic inducers should be considered whenever possible for integrase strand transfer inhibitor (INSTI)-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.

ADJUST DOSING INTERVAL: Food does not appear to substantially alter the pharmacokinetics of tipranavir. When tipranavir capsules or oral solution was coadministered with ritonavir capsules at steady-state, no clinically significant changes in tipranavir peak plasma concentration (Cmax) and systemic exposure (AUC) were observed under fed conditions (500 to 682 kcal, 23% to 25% calories from fat) relative to fasted conditions. The effect of food on tipranavir exposure during coadministration with ritonavir tablets has not been evaluated. High-fat foods may enhance the gastrointestinal absorption of tipranavir. In a multiple-dose study, administration of tipranavir capsules with a high-fat meal (868 kcal, 53% from fat, 31% from carbohydrates) increased the oral bioavailability of tipranavir by 31% compared to administration with toast and skimmed milk, but did not significantly affect tipranavir Cmax. Thus, tipranavir may be safely taken with standard or high-fat meals.

MANAGEMENT: Tipranavir coadministered with low-dose ritonavir should be taken with food to improve the gastrointestinal tolerability of ritonavir. According to the product labeling, tipranavir coadministered with ritonavir capsules or solution can be taken with or without meals, whereas tipranavir coadministered with ritonavir tablets must be taken with meals.

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.