Low Antituberculosis Drug Concentrations in HIV-Tuberculosis- Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?
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Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
Antimicrob Agents Chemother
Abstract
Antituberculosis drugs display large pharmacokinetic variability, which
may be influenced by several factors, including body size, genetic differences, and
drug-drug interactions. We set out to determine these factors, quantify their effect,
and determine the dose adjustments necessary for optimal drug concentrations. HIVinfected
Ugandan adults with pulmonary tuberculosis treated according to international
weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2,
and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May
2013 and November 2015, we enrolled 268 patients (148 males) with a median
weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35
(IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret
the data and revealed that patients weighing 55 kg achieved lower concentrations
than those in higher weight bands for all drugs in the regimen. The models predicted
that this imbalance could be solved with a dose increment of one fixed-dose
combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally,
the concomitant use of efavirenz increased isoniazid clearance by 24.1%,
while bioavailability and absorption of rifampin and isoniazid varied up to 30% in
patients on different formulations. Current dosing guidelines lead to lower drug
exposure in patients in the lower weight bands. Simply adding one FDC tablet
to current weight band-based dosing would address these differences in exposure
and possibly improve outcomes. Lower isoniazid exposures due to efavirenz
deserve further attention, as does the quality of currently used drug formulations
of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under
identifier NCT01782950.)
Description
Keywords
Antitubercular drugs, Monolix, Pharmacokinetics, Pharmacometrics
Citation
Sekaggya-Wiltshire C, Chirehwa M, Musaazi J, von Braun A, Buzibye A, Muller D, Gutteck U, Motta I, Calcagno A, Fehr JS, Kambugu A, Castelnuovo B, Lamorde M, Denti P. 2019. Low antituberculosis drug concentrations in HIV-tuberculosis-coinfected adults with low body weight: is it time to update dosing guidelines? Antimicrob Agents Chemother 63:e02174-18. https://doi.org/10 .1128/AAC.02174-18.