Drug Interaction Report

MONITOR: In vitro data suggest that coadministration with potent inhibitors of P-glycoprotein (e.g., cyclosporine) and/or organic anion transporting polypeptide (e.g., cyclosporine, ritonavir) may increase the plasma concentrations of ambrisentan, which is a substrate of these transporters. In healthy volunteers, steady-state coadministration of ambrisentan and cyclosporine resulted in a 2-fold increase in ambrisentan exposure. The interaction has not been studied with other P-gp or OATP inhibitors.

MANAGEMENT: Because ambrisentan is associated with dose-related hepatotoxicity, concomitant use with potent inhibitors of P-gp and/or OATP should be approached with caution. Patients should be advised to notify their physician if they experience signs and symptoms of liver injury such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

ADJUST DOSING INTERVAL: Administration with food may modestly affect the bioavailability of ritonavir from the various available formulations. When the oral solution was given under nonfasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution (within one hour of dosing) with 240 mL of chocolate milk or a nutritional supplement (Advera or Ensure) did not significantly affect the extent and rate of ritonavir absorption. When a single 100 mg dose of the tablet was administered with a high-fat meal (907 kcal; 52% fat, 15% protein, 33% carbohydrates), approximately 20% decreases in mean peak concentration (Cmax) and systemic exposure (AUC) were observed relative to administration after fasting. Similar decreases in Cmax and AUC were reported when the tablet was administered with a moderate-fat meal. In contrast, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate) relative to fasting.

MANAGEMENT: Ritonavir should be taken with meals to enhance gastrointestinal tolerability.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of ombitasvir, paritaprevir, ritonavir, and dasabuvir. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a moderate-fat meal (approximately 600 Kcal; 20% to 30% calories from fat) increased the mean systemic exposure (AUC) by 82%, 211%, 49%, and 30%, respectively. Relative to fasting conditions, administration of ombitasvir, paritaprevir, ritonavir, and dasabuvir with a high-fat meal (approximately 900 Kcal; with 60% calories from fat) increased the mean AUC by 76%, 180%, 44%, and 22%, respectively.

MANAGEMENT: Ombitasvir/paritaprevir/ritonavir plus dasabuvir should always be administered with a meal. The fat or calorie content does not matter.