Clinically Significant Drug Interactions with Dolutegravir

Coauthor: Susa Coffey, MD; Medical Editor, AETC National Resource Center

Dolutegravir, the newly approved integrase inhibitor, has a number of important drug interactions with other medications and nutritional products. Listed below are highlights of some of the ones most likely to be clinically significant.Like raltegravir, dolutegravir is metabolized primarily by UGT1A1, so the number and type of drug-drug interactions are expected to be comparable to those seen with raltegravir. Elvitegravir/cobicistat has more potential drug interactions because of cobicistat's influences on the CYP450 system. More information on drug interactions involving integrase inhibitors appears in the HIV InSite Database of Antiretroviral Drug Interactions and in the package inserts of the three integrase inhibitors.

Efavirenz

Efavirenz decreases plasma dolutegravir levels. If dosed at 50 mg once daily, dolutegravir AUC and Cmindecreased 57% and 75%, respectively. This interaction seems to occur by induction of both CYP450 3A4 and UGT1A1 by efavirenz. To overcome this interaction, the dolutegravir dosage must be increased to 50 mg BID when efavirenz is part of the ARV regimen for integrase-naive patients.

Etravirine

The combination of etravirine and dolutegravir is acceptable only if a specific ritonavir-boosted protease inhibitor is part of the ARV regimen. When etravirine is combined with dolutegravir, the dolutegravir AUC decreases 71% and Cmin decreases 88%. Coadministration of dolutegravir and etravirine with either darunavir/r or lopinavir/r largely reverses this interaction; combination with atazanavir/r is expected to be acceptable. Dolutegravir should not be used with etravirine.

Nevirapine

Avoid concomitant use of nevirapine with any dosage of dolutegravir, owing to insufficient data on which to base recommendations.

Antacids, calcium, and iron supplements

Polyvalent cations, including antacids containing these cations; calcium, iron, or zinc supplements; and buffered medications may chelate dolutegravir and reduce its efficacy. For example, administering antacids simultaneously with dolutegravir lowers dolutegravir AUC and Cmin by 74%. To avoid this interaction, administer dolutegravir at least 2 hours before or 6 hours after administering polyvalent cations. There is no interaction between dolutegravir and proton pump inhibitors.

Rifampin and rifabutin

Rifampin is a potent inducer of CYP450 3A4 and UGT1A1. Rifampin (600 mg) decreases dolutegravir AUC and Cmin by 54% and 72%, respectively; dosing rifampin with dolutegravir at 50 mg BID yields dolutegravir levels that are comparable to those seen when dolutegravir is dosed at 50 mg once daily without concomitant rifampin. Thus, the dolutegravir dosage should be increased to 50 mg BID for integrase-naive patients receiving concomitant rifampin.
Rifabutin lowers dolutegravir Cmin by 30% but does not significantly change the AUC or Cmax. Based on these data, rifabutin (300 mg once daily) may be coadministered with dolutegravir 50 mg once daily.