Drug Interaction Report

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.

GENERALLY AVOID: Administration with a high-fat meal may decrease the oral bioavailability of amprenavir. The mechanism is unknown. In healthy volunteers, consumption of a standardized high-fat meal decreased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amprenavir (1200 mg single oral dose) by 36% and 21%, respectively, compared to administration in the fasted state. The time to reach Cmax (Tmax) was increased 44% following a high-fat meal.

Grapefruit juice does not appear to significantly affect the pharmacokinetics of amprenavir. In 12 healthy volunteers, administration with grapefruit juice (200 mL) decreased the mean peak plasma concentration (Cmax) of amprenavir (1200 mg single oral dose) by 22% compared to water. The median time to reach Cmax (Tmax) was prolonged from 0.75 to 1.13 hours. These pharmacokinetic changes are not thought to be clinically significant, since antiretroviral response is more closely associated with systemic exposure (AUC) and trough plasma concentration (Cmin), which were not affected in the study.

MANAGEMENT: Amprenavir may be taken with or without food, but should not be taken with a high-fat meal.