Drug Interaction Report

ADJUST DOSE: The concomitant administration of tipranavir-ritonavir with omeprazole or esomeprazole may significantly decrease systemic exposure to the proton pump inhibitors. The proposed mechanism is induction of CYP450 2C19 metabolism by tipranavir-ritonavir. In clinical studies, concurrent administration of tipranavir-ritonavir reduced the steady state AUC and Cmax of omeprazole by 71% and 73%, respectively. Esomeprazole, the S-enantiomer of omeprazole, was similarly affected.

MANAGEMENT: If this combination is given concurrently, patients should be monitored for altered clinical efficacy of the proton pump inhibitor. Dose adjustments may be necessary; however, specific dosage recommendations are not available.

ADJUST DOSING INTERVAL: Concurrent administration of antacids or other agents with acid-neutralizing effects may decrease the oral bioavailability of tipranavir and reduce its concentrations in plasma. The mechanism of interaction has not been described. When tipranavir (in combination with low-dose ritonavir) was coadministered with 20 mL of an aluminum- and magnesium-based liquid antacid, tipranavir peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were reduced by 25% to 29%. The clinical significance of these changes is unknown. However, subtherapeutic antiretroviral drug levels may lead to reduced viral susceptibility and development of resistance.

MANAGEMENT: Consideration should be given to separating tipranavir/ritonavir dosing from antacid administration to prevent reduced absorption of tipranavir.

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.