Drug Interaction Report

MONITOR: Coadministration of tenofovir disoproxil fumarate with telaprevir may increase the plasma concentrations of tenofovir. The mechanism of interaction has not been described. In 16 study subjects, administration of tenofovir DF (300 mg once daily) in combination with telaprevir (750 mg every 8 hours) for 7 days increased the tenofovir peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 30% and the trough plasma concentration (Cmin) by 41% compared to administration alone. The Cmax, AUC and Cmin of telaprevir did not change significantly. When the same dosage of tenofovir DF was given in combination with both efavirenz (600 mg once daily) and telaprevir (1125 mg every 8 hours) for 7 days to fifteen study subjects, tenofovir Cmax, AUC and Cmin increased by an average of just 22%, 10% and 17%, respectively. Similar results were observed when the telaprevir dosage was changed to 1500 mg every 12 hours and administered with tenofovir DF and efavirenz.

MANAGEMENT: Increased clinical and laboratory monitoring are warranted when tenofovir DF is coadministered with telaprevir. Treatment with tenofovir DF should be discontinued in patients who develop tenofovir-related toxicities such as renal impairment or lactic acidosis and severe hepatomegaly with steatosis.

MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or uridine diphosphate glucuronosyltransferase (UGT) 1A1 may increase the plasma concentrations of bictegravir. According to the product labeling, bictegravir is a substrate of both CYP450 3A4 and UGT1A1; however, the extent to which each enzymatic pathway contributes to the metabolic clearance of bictegravir has not been reported. In healthy volunteers studied under fasted conditions, administration of a single 75 mg dose of bictegravir during treatment with the potent CYP450 3A4 inhibitor voriconazole (300 mg twice daily) increased mean bictegravir peak plasma concentration (Cmax) and systemic exposure (AUC) by 9% and 61%, respectively, compared to administration of bictegravir alone. In addition, in healthy volunteers studied under fed conditions, administration of a single 75 mg dose of bictegravir during treatment with the potent CYP450 3A4 and UGT1A1 inhibitor atazanavir (400 mg once daily) increased mean bictegravir AUC by 315%, compared to administration of bictegravir alone.

MANAGEMENT: Caution is advised when bictegravir is used with CYP450 3A4 and UGT1A1 inhibitors. Patients should be monitored for increased adverse effects such as diarrhea, nausea, and vomiting.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of telaprevir. When given with a meal containing 533 kcal and 21 g fat, telaprevir systemic exposure (AUC) increased by 237% compared to administration under fasting conditions. The type of meal also affects the exposure to telaprevir. Relative to fasting, telaprevir AUC increased by approximately 117% with a low-fat meal (249 kcal; 3.6 g fat) and 330% with a high-fat meal (928 kcal; 56 g fat). In Phase 3 clinical trials, telaprevir doses were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat.

MANAGEMENT: Telaprevir should be administered with food containing approximately 20 grams of fat. Patients should be advised that the fat content of the meal or snack is critical to the absorption of telaprevir. Food taken with telaprevir should be ingested within 30 minutes prior to each dose. Examples of some foods that could be taken with telaprevir include: bagel with cream cheese; half cup of nuts; 3 tablespoons of peanut butter; 1 cup of ice cream; 2 ounces of American or cheddar cheese; 2 ounces of potato chips; or half cup of trail mix.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.