Drug Interaction Report

MONITOR: Coadministration with inducers of uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase or UGT) enzymes may decrease the systemic exposure and effects of aprocitentan, which is primarily metabolized by UGT1A1 and UGT2B7. Some UGT inducers are associated with similar adverse effects to those of aprocitentan, such as hepatotoxicity (e.g., alcohol, carbamazepine, efavirenz, fosphenytoin, phenytoin, rifampin). It is unclear if the use of aprocitentan with these substances could increase the risk of similar adverse effects. Clinical data examining aprocitentan with inducers of UGT are not available.

MANAGEMENT: Caution and clinical monitoring for reduced efficacy may be advised if aprocitentan is used with a UGT inducer. If the UGT inducer also shares a similar adverse effect profile with aprocitentan, like hepatotoxicity, additional monitoring for the adverse effect in question may also be recommended. Additional monitoring may also be beneficial if a UGT inducer is added to or withdrawn from the patient's regimen during aprocitentan therapy.

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.