Drug Interaction Report

MONITOR: Coadministration with istradefylline may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) transporter. The proposed mechanism is inhibition of P-glycoprotein-mediated drug efflux by istradefylline. When a single dose of the P-gp probe substrate digoxin (0.4 mg) was administered with istradefylline (40 mg daily for 21 days), the Cmax and total systemic exposure (AUC(inf)) of digoxin was increased by 33% and 21%, respectively, when compared with digoxin alone.

MANAGEMENT: Caution is advised when istradefylline is used concurrently with drugs that are known P-gp substrates, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever istradefylline is added to or withdrawn from therapy.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.

ADJUST DOSE: Smoking tobacco may decrease the steady-state systemic exposure of istradefylline by 38% to 54%.

MANAGEMENT: The possibility of reduced therapeutic effects of istradefylline should be considered in smokers. The manufacturer recommends an istradefylline dosage of 40 mg once daily in patients who smoke 20 or more cigarettes (or the equivalent amount of another tobacco product) per day.