Drug Interaction Report

MONITOR: Coadministration of istradefylline may increase the serum concentrations of digoxin. The proposed mechanism is istradefylline inhibition of the P-glycoprotein-mediated renal tubular secretion of digoxin. When a single dose of digoxin (0.4 mg) was administered with istradefylline (40 mg daily for 21 days), the peak plasma concentration (Cmax) and total systemic exposure (AUC(inf)) of digoxin was increased by 33% and 21%, respectively, when compared with digoxin alone.

MANAGEMENT: Serum digoxin levels and pharmacologic effects should be closely monitored following the addition or withdrawal of istradefylline, and the digoxin dosage adjusted as needed. Patients should be advised to seek medical attention if they experience signs of digoxin toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeat.

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.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.