Coadministration decreased dolutegravir AUC, Cmax and Ctrough by 57%, 39% and 75%, respectively by induction of UGT1A1 and CYP3A enzymes. The recommended adult dose of dolutegravir is 50 mg twice daily when co-administered with efavirenz. In paediatric patients the weight-based once daily dose should be administered twice daily. In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered.

Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.  

 

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, dolutegravir did not appear to affect the pharmacokinetics of efavirenz. Adjust dose of dolutegravir to 50 mg twice daily for treatment-naïve and treatment experienced, INSTI-naïve patients. In pediatric patients, increase the weight-based dose to twice daily. Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI associated resistance substitutions or clinically suspected INSTI resistance) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to dolutegravir or other coadministered antiretroviral agents.

 

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.