Drug Interactions between Paxlovid and rifampin

GENERALLY AVOID: Coadministration with rifampin may decrease the plasma concentrations of ritonavir. The mechanism is rifampin induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of ritonavir. In seven study subjects, rifampin (300 or 600 mg daily for 10 days) decreased the mean steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ritonavir (500 mg every 12 hours) by 25% and 35%, respectively, compared to data from nine control subjects. The clinical significance of this interaction is unknown but may be minor. In a small pilot study, protease inhibitor-naive, advanced HIV-infected patients received antituberculosis therapy with isoniazid, pyrazinamide, and rifampin (600 mg/day) for 2 months before starting concomitant antiretroviral treatment with ritonavir (600 mg twice a day) and two nucleoside reverse transcriptase inhibitors (NRTIs). The patients tolerated and responded well to both therapy during follow-up of up to 40 weeks, and drug levels were generally within normal limits relative to historical data and deemed therapeutically adequate. No additive hepatotoxic effects were apparent, with only mild elevations in serum transaminase levels reported (less than a 3-fold increase of normal values).

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, ritonavir labeling recommends that alternative antimycobacterial agents such as rifabutin be considered in HIV patients treated with ritonavir. However, some experts, as well as CDC guidelines, suggest that usual antituberculous dosages of rifampin may be used with ritonavir 400 to 600 mg twice daily in combination with one or more NRTIs. Rifampin should not be used with low-dose ritonavir (i.e. 100 mg twice daily given as a pharmacokinetic booster of other protease inhibitors), since low-dose ritonavir does not prevent rifampin-induced decreases in the concentrations of lopinavir and presumably other protease inhibitors. In general, treatment of tuberculosis (TB) in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related TB should be consulted, and TB and HIV care providers should work in close coordination throughout treatment.

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.