Drug Interaction Report

MONITOR: Coadministration with delavirdine may increase the plasma concentrations of ritonavir. The mechanism is delavirdine inhibition of ritonavir metabolism via CYP450 3A4. In 12 HIV-infected patients stabilized on antiretroviral therapy that included ritonavir 600 mg twice a day as the sole protease inhibitor, addition of delavirdine (400 mg three times a day for 21 days) increased the mean peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and trough plasma concentration (Cmin) of ritonavir by 66%, 64% and 81%, respectively, compared to baseline. Ritonavir did not significantly affect the steady-state concentrations of delavirdine when compared to those from a reference database for delavirdine administered with food. The combination was well tolerated in the study, and no serious adverse event occurred. With respect to lower dosages of the combination, no significant interaction occurred when delavirdine 400 mg was administered with ritonavir 300 mg twice a day in healthy volunteers. However, it is uncertain whether these data are applicable to HIV-infected patients, as altered patterns of drug metabolism have been observed in this population.

MANAGEMENT: Appropriate dosages for the combination of ritonavir and delavirdine with respect to safety and efficacy have not been established. Patients given the combination should be advised to notify their physician if they experience potential signs of ritonavir intolerance such as severe nausea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias. The effect of delavirdine on lower dosages of ritonavir (e.g., 100 or 200 mg twice a day as a pharmacokinetic booster of other protease inhibitors) in HIV-infected patients is unknown.

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.