Drug Interaction Report

Theoretically, coadministration with inhibitors of UGT1A or CYP450 3A4 isoenzymes may increase 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. Potent CYP450 3A4 inhibitors such as boceprevir (800 mg every 8 hours) and telaprevir (750 mg every 8 hours) had no significant effects on the pharmacokinetics of dolutegravir given at 50 mg once daily. The interaction has not been studied or reported with UGT1A1 inhibitors such as nilotinib, regorafenib, and sorafenib. However, it is possible that simultaneous inhibition of UGT1A1 and CYP450 3A4 may lead to a clinically significant interaction with dolutegravir. In 12 study subjects, administration of dolutegravir (30 mg once daily) with the dual UGT1A1 and CYP450 3A4 inhibitor, atazanavir (400 mg once daily), increased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours postdose) by 50%, 91% and 180%, respectively, compared to administration without atazanavir. When the same dosage of dolutegravir was given with atazanavir/ritonavir 300 mg/100 mg once daily, the Cmax, AUC and Cmin of dolutegravir increased by 34%, 62% an 121%, respectively. Because safety data regarding increased dolutegravir exposures are limited, caution may be advisable if dolutegravir is used in combination with both a UGT1A1 inhibitor and a CYP450 3A4 inhibitor.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to 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.