Drug Interactions between cariprazine and nirmatrelvir / ritonavir

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.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of cariprazine. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of cariprazine by certain compounds present in grapefruit. When cariprazine (0.5 mg/day) was coadministered with the potent CYP450 3A4 inhibitor, ketoconazole (400 mg/day), cariprazine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 3.5- and 4-fold, respectively, while Cmax and AUC of DDCAR increased by approximately 1.5-fold each. The Cmax and AUC of another active metabolite, desmethyl cariprazine (DCAR), decreased by approximately one-third. The interaction has not been studied with grapefruit juice. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to cariprazine may increase the risk of adverse effects such as extrapyramidal symptoms, cognitive and motor impairment, hyperglycemia, dyslipidemia, weight gain, orthostatic hypotension, leucopenia, neutropenia, seizures, and dysphagia.

MANAGEMENT: Patients should avoid the consumption of grapefruit and grapefruit juice during treatment with cariprazine.