Drug Interaction Report

CONTRAINDICATED: Coadministration with drugs that are strong inducers of CYP450 3A4 may decrease the plasma concentrations of ritonavir and result in a potential loss of virologic response. The proposed mechanism is increased clearance due to induction of CYP450 3A4, which is the isoenzyme primarily responsible for the metabolism of ritonavir.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, concomitant use of ritonavir with drugs that are strong inducers of CYP450 3A4 is considered contraindicated.

CONTRAINDICATED: Coadministration with drugs that are potent inducers of CYP450 3A4 may decrease the plasma concentrations of nirmatrelvir and result in a potential loss of virologic response. The proposed mechanism is increased clearance due to induction of CYP450 3A4, which is the isoenzyme primarily responsible for the metabolism of nirmatrelvir. According to the manufacturer, coadministration of nirmatrelvir-ritonavir (300 mg-100 mg twice daily for 5 doses) with the potent CYP450 3A4 inducer carbamazepine (300 mg twice daily for 16 doses) (n=9) decreased the systemic exposure (AUC) and peak plasma concentration (Cmax) of nirmatrelvir by approximately 55% and 43%, respectively. Data are unavailable for other, less potent inducers. In addition, the plasma concentrations and pharmacologic effects of the concomitant inducer may be affected; however, clinical data are lacking.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of nirmatrelvir-ritonavir with drugs that are potent inducers of CYP450 3A4 is considered to be contraindicated.

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.