Drug Interactions between nirmatrelvir / ritonavir and voriconazole

CONTRAINDICATED: Coadministration with ritonavir may significantly decrease or increase the plasma concentrations of voriconazole. The proposed mechanism may involve ritonavir-mediated induction of voriconazole metabolism via the CYP450 isoenzymes 2C19 and 2C9. Voriconazole is primarily metabolized via CYP450 2C19, and to a lesser extent, by CYP450 2C9 and 3A4. In a randomized, placebo-controlled study in healthy adult male subjects (n=29), high-dose ritonavir (400 mg twice daily for 10 days) administered with oral voriconazole (400 mg twice daily for one day, then 200 mg twice daily for 9 days) decreased the mean steady-state voriconazole peak plasma concentration (Cmax) and systemic exposure (area under the concentration-time curve from 0 to 12 hours, or AUC (0-12)) by 68% and 83%, respectively. Low-dose ritonavir (100 mg every 12 hours for 10 days) administered with the same oral voriconazole regimen in healthy adult male subjects (n=17) decreased the mean steady-state Cmax and AUC (0-12) of voriconazole by 24% and 39%, respectively. However, the opposite effect may occur in patients who are poor metabolizers of CYP450 2C19. The net effect in these patients may be increased exposure to voriconazole via ritonavir-mediated inhibition of CYP450 3A4. In the high-dose ritonavir study above, one subject had an increased voriconazole exposure of 2.5-fold. In the low-dose ritonavir study, 4 subjects showed increased voriconazole exposure; three of these had slight increases (10% to 42%), but one subject had an approximately 3.5-fold increase in voriconazole exposure. Although voriconazole is also considered a strong inhibitor of CYP450 3A4 and an inhibitor of CYP450 2C19 and 2C9, the pharmacokinetics of high-dose ritonavir were not significantly affected by voriconazole; mean steady-state Cmax and AUC (0-12) of low-dose ritonavir decreased slightly by approximately 24% and 14%, respectively, during coadministration with oral voriconazole.

MANAGEMENT: The use of voriconazole in combination with high-dose ritonavir (400 mg or more every 12 hours) is considered contraindicated. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should also be avoided, unless the benefit justifies the risk.