Isoniazid/Rifampicin Associated With Limited Efavirenz Pharmacokinetic Changes

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INH/RIF coadministration was associated with limited changes in efavrienz concentrations in the ENCORE-1 study, regardless of <i>CYP2B6</i> genotype.
INH/RIF coadministration was associated with limited changes in efavrienz concentrations in the ENCORE-1 study, regardless of CYP2B6 genotype.

The coadministration of efavirenz 400 mg with isoniazid and rifampicin as anti-tuberculosis treatment in patients living with HIV was associated with limited efavirenz area under the curve changes, as well as minimum effective efavirenz blood concentrations (<800 ng/mL) regardless of polymorphic enzyme cytochrome P450 2B6 (CYP2B6) genotype, according to a study published in Clinical Infectious Diseases.

The current study sought to evaluate the coadministration of efavirenz 400 mg with isoniazid and rifampicin for patients living with HIV, primarily to test the pharmacokinetic parameters and genetic polymorphisms of efavirenz administered with and without isoniazid and rifampicin.

The secondary objectives were to investigate the tolerability and safety of efavirenz 400 mg combined with tenofovir disoproxil fumarate and emtricitabine and describe the pharmacogenetics related to the CYP2B6 genotype of the participants.

Study participants (N=26) were all living with HIV and without TB, and had been receiving tenofovir disoproxil fumarate and emtricitabine with efavirenz 600 mg for 12 or more weeks prior. From day 1 to day 14, dosages of efavirenz were reduced to 400 mg, and then from day 15 to day 98, co-formulated once-daily isoniazid and rifampicin weres added to the efavirenz.

From baseline to day 42, efavirenz therapeutic drug monitoring (TDM) tests were performed 10 to 14 hours post-dose. The testing was reduced to once weekly for participants with stable blood concentrations.

Overall, 22 participants completed the study, and all maintained <50 copies/mL viral loads throughout. Geometric mean ratio of day 14 and 42 maximum plasma concentrations, area under the curve, and 24 hours post-dose concentrations were 0.91 (90% CI, 0.83 to 0.99), 0.91 (90% CI, 0.79 to 1.05), and 0.85 (90% CI, 0.72 to 0.99), respectively.

Geometric mean ratios (90% CI) of day 98/day 42 vs day 98/day 14 maximum plasma concentrations, area under the curve, and 24 hours post-dose concentrations were 0.95 (0.86 to 1.05) vs 0.92 (0.83 to 1.01), 0.88 (0.75 to 1.03) vs 0.84 (0.75 to 0.93), and 0.84 (0.72 to 0.99) vs 0.75 (0.62 to 0.92), respectively.

Although 11 of the 22 study participants carried CYP2B6 genetic polymorphisms associated with slow efavirenz metabolism, minimum effective blood concentrations were nevertheless maintained throughout the study.

Study investigators conclude that “[efavirenz 400 mg] can be coadministered with [isoniazid and rifampicin]-containing anti-TB treatment and it can be used extensively in low- and middle-income countries to reduce drug manufacture costs and HIV treatment discontinuations due to adverse events.”

This study was supported by a research grant from Mylan through OPTIMIZE.

Reference

Cerrone M, Wang X, Neary M, et al. Pharmacokinetics of Efavirenz 400 mg Once Daily Coadministered With Isoniazid and Rifampicin in Human Immunodeficiency Virus-infected Individuals [published online August 6, 2018]. Clin Infect Dis. doi: 10.1093/cid/ciy49

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