Pharmacokinetics of Efavirenz 400 mg Once Daily Coadministered With Isoniazid and Rifampicin in Human Immunodeficiency Virus-Infected Individuals.

Background

The World Health Organization recommends efavirenz 400 mg (EFV400) as first-line antiretroviral therapy, with a disclaimer that no data with anti-tuberculosis (TB) treatment exist. Many people living with human immunodeficiency virus (PLWH) require TB treatment with isoniazid (INH) and rifampicin (RIF), which affect cytochrome P450 and antiretroviral exposure.

Methods

PLWH receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/EFV 600 mg with a viral load (VL) <50 copies/mL switched to TDF/FTC/EFV400. Genetic polymorphisms and pharmacokinetic (PK) parameters of EFV400 without (PK1) and with INH/RIF following 4 (PK2) and 12 (PK3) weeks of coadministration were evaluated.

Results

Twenty-six PLWH were enrolled; 22 completed PK2. All maintained VL <50 copies/mL throughout the study. Geometric mean ratio (GMR) PK2/PK1 of EFV400 maximum plasma concentration (Cmax), area under the curve (AUC), and concentration at 24 hours postdose (C24h) were 0.91 (90% confidence interval [CI], .83-.99), 0.91 (90% CI, .79-1.05), and 0.85 (90% CI, .72-.99), respectively. GMRs (90% CI) of PK3/PK2 and PK3/PK1 Cmax, AUC, and C24h were 0.95 (.86-1.05) and 0.92 (.83-1.01), 0.88 (.75-1.03) and 0.84 (.75-.93), and 0.84 (.72-.99) and 0.75 (.62-.92), respectively. Eleven of 22 participants carried polymorphisms in the CYP2B6 gene associated with slow EFV metabolism.

Conclusions

INH/RIF coadministration was associated with limited changes in EFV400 AUC (<25%), and EFV400 concentrations were maintained within ranges of those measured in PLWH in the ENCORE-1 study, irrespective of CYP2B6 genotype. The coadministration of EFV400 with anti-TB treatment can be considered and this is being confirmed in PLWH with TB.

Clinical Trials Registration

NCT02832778.