Drug Interaction Report

CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of rilpivirine, which is primarily metabolized by the isoenzyme. In 16 study subjects given rilpivirine (150 mg once daily) with the potent CYP450 3A4 inducer rifampin (600 mg once daily), mean rilpivirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were reduced by 69%, 80% and 89%, respectively. The pharmacokinetics of rifampin and its metabolite, 25-desacetylrifampin, were not significantly altered.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, concomitant use of rilpivirine with potent CYP450 3A4 inducers is considered contraindicated.

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.

GENERALLY AVOID: Coadministration with grapefruit or grapefruit juice may increase the plasma concentrations of rilpivirine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. In 15 study subjects given rilpivirine (150 mg once daily) with the potent CYP450 3A4 inhibitor ketoconazole (400 mg once daily), mean rilpivirine peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were increased by 30%, 49% and 76%, respectively. In 16 study subjects given a single 500 mg dose of a less potent CYP450 3A4 inhibitor chlorzoxazone two hours after rilpivirine (150 mg once daily), mean rilpivirine Cmax, AUC, and Cmin were increased by 17%, 25%, and 18%, respectively. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

ADJUST DOSING INTERVAL: The administration of rilpivirine in a fasting state may decrease its oral absorption. Under fasted conditions, the systemic exposure to rilpivirine was 40% lower compared to normal or high-fat caloric meals (533 to 928 Kcal). The systemic exposure was 50% lower when rilpivirine was taken with a protein-rich nutritional beverage.

MANAGEMENT: Coadministration of grapefruit or grapefruit juice with rilpivirine should preferably be avoided. For optimal absorption, it is recommended to take rilpivirine on a regular schedule with a meal.

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.