Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: A population pharmacokinetic modelling and simulation study

Krina Mehta, Shruthi Ravimohan, Jotam G. Pasipanodya, Shashikant Srivastava, Chawangwa Modongo, Nicola M. Zetola, Drew Weissman, Vijay Ivaturi, Tawanda Gumbo, Gregory P. Bisson, Christopher Vinnard

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: Reduced ethambutol serum concentrations are commonly observed among TB patients co-infected with HIV and may lead to treatment failure. Objectives: To perform a population pharmacokinetic study of ethambutol in HIV/TB patients, and to evaluate an intensified ethambutol weight-based dosing strategy to support pharmacokinetic target attainment. Methods: We conducted a prospective study of ethambutol pharmacokinetics among HIV/TB patients administered first-line TB treatment in Botswana, with study visits before and after initiation of ART. Clinical and disease status markers, including HIV-Associated systemic immune activation and gut dysfunction biomarkers, were evaluated as covariates of ethambutol pharmacokinetic parameters in non-linear mixed effects analysis. Monte Carlo simulations were performed to compare pharmacokinetic target attainment under standard and intensified weight-based ethambutol dosing strategies. Results: We studied 40 HIV/TB patients prior to initiation of ART, of whom 24 returned for a second visit a median of 33 days following ART initiation. Ethambutol serum concentrations were best explained by a two-compartment model with first-order elimination, with a significant improvement in oral bioavailability following ART initiation. In Monte Carlo simulations, a supplementary ethambutol dose of 400 mg daily led to >2-fold improvements in pharmacokinetic target attainment probabilities in lung tissue, both before and after ART initiation. Conclusions: Low serum ethambutol concentrations were commonly observed among HIV/TB patients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TB patients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.

Original languageEnglish (US)
Pages (from-to)2994-3002
Number of pages9
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number10
DOIs
StatePublished - Oct 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

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