Drug Interaction Report

ADJUST DOSE: Coadministration with potent inducers of UGT1A and CYP450 3A4 isoenzymes such as rifampin may significantly decrease the plasma concentrations of dolutegravir, which is primarily metabolized by UGT1A1 with some contribution from CYP450 3A4. Dolutegravir is also a substrate of UGT1A3, UGT1A9, and P-glycoprotein in vitro. In 11 study subjects, administration of dolutegravir 50 mg twice daily with rifampin 600 mg once daily decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 43%, 54% and 72%, respectively, compared to administration without rifampin. However, when compared to dolutegravir taken at the normally recommended dosage of 50 mg once daily, coadministration of dolutegravir and rifampin at the aforementioned dosages increased dolutegravir Cmax, AUC and Cmin by 18%, 33% and 22%, respectively.

MANAGEMENT: When prescribed in combination with rifampin, the dosage of dolutegravir should be increased to 50 mg twice daily for both adults and pediatric patients 12 years of age and older who weigh at least 40 kg. The safety and efficacy of dosages above 50 mg twice daily have not been evaluated. For concomitant use of rifampin with fixed-dose combination products containing dolutegravir, it is recommended to administer an additional 50 mg daily dose of dolutegravir approximately 12 hours from the combination product. Alternatives to rifampin that are not metabolic inducers should be considered whenever possible for integrase strand transfer inhibitor (INSTI)-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.

GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

Food increases the extent of absorption and slows the rate of absorption of dolutegravir. When administered with a low-, moderate- or high-fat meal, dolutegravir peak plasma concentration (Cmax) increased by 46%, 52% and 67%, systemic exposure (AUC) increased by 33%, 41% and 66%, and time to reach Cmax (Tmax) increased from 2 hours to 3, 4 and 5 hours, respectively, compared to administration under fasted conditions. Dolutegravir may be taken with or without food.