Krina Mehta1, Shruthi Ravimohan2, Jotam G Pasipanodya3, Shashikant Srivastava3, Chawangwa Modongo4, Nicola M Zetola4, Drew Weissman5, Vijay Ivaturi1, Tawanda Gumbo3, Gregory P Bisson5, Christopher Vinnard6. 1. Center for Translational Medicine, University of Maryland, Baltimore, MD, USA. 2. Bristol-Myers Squibb, Lawrenceville, NJ, USA. 3. Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA. 4. Pennsylvania Botswana-UPenn Partnership, Gaborone, Botswana. 5. University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. 6. Public Health Research Institute, New Jersey Medical School, Newark, NJ, USA.
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.
BACKGROUND: Reduced ethambutol serum concentrations are commonly observed among TBpatients co-infected with HIV and may lead to treatment failure. OBJECTIVES: To perform a population pharmacokinetic study of ethambutol in HIV/TBpatients, 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/TBpatients 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/TBpatients 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/TBpatients in Botswana, and the oral bioavailability of ethambutol increased following ART initiation. Supplementary ethambutol dosing among HIV/TBpatients may provide a strategy to optimize anti-TB treatment regimens in this high-risk population.
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