Drug Interaction Report

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.

ADJUST DOSE: Coadministration of a protease inhibitor (PI) in combination with bosentan may increase the plasma concentration of bosentan and decrease that of the PI, unless ritonavir is included as a pharmacokinetic booster. Both PIs and bosentan are primarily metabolized by CYP450 3A4. Because PIs are also inhibitors of CYP450 3A4, they can inhibit the metabolic clearance of bosentan. Conversely, bosentan may induce the metabolism of PIs, although the effects are probably not significant in the presence of ritonavir, which is a potent CYP450 3A4 inhibitor.

MANAGEMENT: Protease inhibitors should generally not be used in combination with bosentan unless ritonavir is also added as a pharmacokinetic booster. Dose adjustment of bosentan has been recommended. In patients who are starting bosentan and have been receiving PI therapy for at least 10 days, it has been recommended to start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. When starting PI therapy in patients already on bosentan, it has been recommended to discontinue bosentan for at least 36 hours prior to initiation of PI therapy. After at least 10 days following the initiation of PI therapy, bosentan may be resumed at 62.5 mg once daily or every other day based upon individual tolerability. According to some authorities, use of the fixed combination atazanavir-cobicistat with bosentan is not recommended.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.