Drug Interactions between bosentan and nirmatrelvir / ritonavir

ADJUST DOSE: Coadministration with the pharmacokinetic boosters cobicistat and ritonavir may significantly increase the plasma concentrations of bosentan, particularly during the first few days of combined use. The proposed mechanism is inhibition of the OATP-mediated uptake of bosentan into hepatocytes. In healthy volunteers, coadministration of bosentan (125 mg twice daily) and lopinavir-ritonavir (400-100 mg twice daily) increased the trough concentrations of bosentan on Days 4 and 10 by approximately 48-fold and 5-fold, respectively, compared to those measured after administration of bosentan alone. Bosentan had no significant effect on the pharmacokinetics of lopinavir-ritonavir. In contrast, bosentan may decrease the plasma concentration of cobicistat via induction of CYP450 3A4, which may result in the loss of therapeutic effects and development of resistance.

MANAGEMENT: The dosage of bosentan should be adjusted when used in combination with cobicistat or ritonavir. In patients who have been receiving cobicistat or ritonavir for at least 10 days when bosentan is prescribed, the latter should be initiated at 62.5 mg once daily or every other day depending on individual tolerability. Conversely, in patients who have been receiving bosentan when cobicistat or ritonavir is prescribed, the manufacturers recommend that use of bosentan be discontinued for at least 36 hours prior to initiating the pharmacokinetic booster. After at least 10 days following the initiation of cobicistat or ritonavir, bosentan may be resumed at 62.5 mg once daily or every other day based upon individual tolerability. There is limited experience with abrupt discontinuation of bosentan. Although no evidence for acute rebound has been observed, gradual dose reduction (62.5 mg twice daily for 3 to 7 days) should be considered to minimize the potential for clinical deterioration.

MONITOR: Coadministration with drugs that are inducers of CYP450 3A4 may decrease the plasma concentrations of nirmatrelvir which is primarily metabolized by the isoenzyme. 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, nirmatrelvir-ritonavir should be used cautiously with agents that induce CYP450 3A4. Antiviral response should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy.