Drug Interaction Report

MONITOR: Coadministration with tipranavir in combination with ritonavir may alter the pharmacokinetics of immunosuppressants that are dual substrates of CYP450 3A4 and P-glycoprotein. The potential changes cannot be predicted due to the conflicting effects of tipranavir and ritonavir on CYP450 3A4 and P-glycoprotein. Specifically, ritonavir is a potent inhibitor of CYP450 3A4 and tend to reduce clearance of substrate drugs, while tipranavir is a potent inducer of P-glycoprotein intestinal efflux transporters and tend to increase clearance of substrate drugs.

MANAGEMENT: Caution is advised if immunosuppressants such as cyclosporine, sirolimus, and tacrolimus are coadministered with tipranavir/ritonavir. More frequent concentration monitoring of these drugs is recommended until blood levels have been stabilized.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

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.