Pharmacokinetics of efavirenz 400 mg once daily coadministered with isoniazid and rifampicin in human immunodeficiency virus-infected individuals
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2019-02-01
Date Acceptance
2018-06-18
Citation
Clinical Infectious Diseases, 2019, 68 (3), pp.446-452
ISSN
1058-4838
Publisher
Oxford University Press (OUP)
Start Page
446
End Page
452
Journal / Book Title
Clinical Infectious Diseases
Volume
68
Issue
3
Copyright Statement
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30084943
PII: 5067052
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
Infectious Diseases
Microbiology
low-dose efavirenz
pharmacokinetics
tuberculosis
isoniazid/rifampicin
HIV
TUBERCULOSIS TREATMENT
PLASMA-CONCENTRATIONS
DOUBLE-BLIND
CYP2B6
EXPOSURE
POLYMORPHISMS
EFFICACY
WEIGHT
IMPACT
06 Biological Sciences
11 Medical and Health Sciences
Microbiology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2018-08-06