Coadministration of efavirenz and dolutegravir decreased dolutegravir AUC, Cmax and Ctrough by 57%, 39% and 75%, respectively, due to induction of UGT1A1 and CYP3A. There was no effect on efavirenz when compared to historical controls. Since the dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz, the co-administration of efavirenz with Triumeq is not recommended.

The dolutegravir dose (50 mg) in Triumeq is insufficient when coadministered with efavirenz as it may decrease dolutegravir concentrations. The recommended dolutegravir dosage regimen is 50 mg twice daily. An additional dolutegravir 50-mg tablet, separated by 12 hours from Triumeq, should be taken. Coadministration of efavirenz (600 mg once daily) and dolutegravir (50 mg once daily) to 12 subjects decreased dolutegravir Cmax, AUC and Ctrough by 39%, 57% and 75%, respectively. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of efavirenz.

Coadministration of dolutegravir (50 mg once daily) and efavirenz (600 mg once daily) was studied in 12 HIV-negative subjects. In the presence of efavirenz, dolutegravir AUC, Cmax and Ctrough decreased by 57%, 39%, 75%, respectively (likely via UGT and CYP3A induction by efavirenz). However, dolutegravir concentrations remained 4-5 fold higher than the protein-adjusted IC90 for the wild type virus and the authors concluded no dose adjustment was required when dolutegravir and efavirenz were given concomitantly in integrase naïve patients.

Efavirenz is primarily metabolized by CYP2B6. This study evaluated the effect of CYP2B6 genotype on the pharmacokinetic interaction between efavirenz and dolutegravir. Twelve HIV-negative adults received dolutegravir 50 mg once daily for 5 days (period 1), followed by efavirenz 600 mg + dolutegravir 50 mg once daily for 14 days (period 2). Nine individuals were genotyped for rs3745274 (1/*1, *1/*6 or *6/*6). Dolutegravir Ctrough decreased by 85% in CYP2B6 slow and intermediate metabolizers and by 60% in CYP2B6 normal metabolizers. Efavirenz half-life was 2.7 times higher in CYP2B6 slow (39.1 hours, 95% CI 17.1-89.5 hours) than in normal metabolizers (14.3 hours, 95% CI 12.6-16.1 hours) and was 24.6 hours in the intermediate metabolizers. This study demonstrated a strong association between CYP2B6 slow metabolizer genotype (and resulting increased efavirenz exposure) with plasma dolutegravir concentrations. Switch from efavirenz to dolutegravir is of little concern for individuals with viremia well controlled because at no time both dolutegravir and efavirenz concentrations simultaneously fall below their respective clinical target concentrations. However, switch could be problematic in individuals with uncontrolled viremia and efavirenz resistances in which case efavirenz will not protect dolutegravir during its period of subtherapeutic exposure. The safest strategy would be to switch from efavirenz to dolutegravir when HIV is well suppressed. If HIV replication is not controlled and if resistances to efavirenz are present, prescription of dolutegravir 50 mg twice daily might be considered up to 2 weeks after the switch. The same strategy might be applied to CYP2B6 slow metabolizers.

Dolutegravir is the preferred second-line antiretroviral backbone agent for people living with HIV failing a first-line efavirenz-based regimen. Efavirenz induces metabolism and was shown to reduce dolutegravir exposure for up to 14 days when switching from an efavirenz-based regimen. Exposure to sub-therapeutic dolutegravir concentrations in people living with HIV failing efavirenz-based first-line antiretrovirals could select for dolutegravir resistance mutations. This study evaluated dolutegravir trough concentrations after switching from a failing first-line efavirenz-based regimen to assess the need for a lead-in supplemental dose of dolutegravir. Participants failing a first-line efavirenz-based regimen were randomized to receive supplemental dolutegravir 50 mg or placebo for 14 days post-switch to tenofovir/lamivudine/dolutegravir (TLD). Efavirenz was measured at baseline and days 3, 7 and 14 and dolutegravir trough concentrations at days 3, 7, 14 and 28. 36 participants were enrolled: 11 in the placebo arm and 25 in the supplemental arm. One participant in the supplemental dolutegravir arm and none in the placebo arm had a dolutegravir trough concentration below the PA-IC90 (64 ng/mL) at day 3. There were no slow metabolizers in the placebo arm and 5 in the supplemental arm. In summary, no participants in the placebo arm had dolutegravir trough concentrations below the PA-IC90. Prolonged efavirenz induction effect in CYP2B6 slow metabolizers contributed to lower dolutegravir trough concentrations at day 28 in the supplemental arm. This finding does not support the need for a supplemental dolutegravir dose when switching from a failing first-line efavirenz based regimen.

The effect of abacavir (300 mg twice daily) on the pharmacokinetics of indinavir was assessed in HIV+ subjects receiving indinavir 1000 mg three times daily with efavirenz 600 mg once daily, or indinavir/efavirenz 1200/300 mg twice daily. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz.