%0 Journal Article
%9 ACL : Articles dans des revues avec comité de lecture répertoriées par l'AERES
%A Smythe, W.
%A Merle, C. S.
%A Rustomjee, R.
%A Gninafon, M.
%A Lo, M. B.
%A Bah-Sow, O.
%A Olliaro, P. L.
%A Lienhardt, Christian
%A Horton, J.
%A Smith, P.
%A McIlleron, H.
%A Simonsson, U. S. H.
%T Evaluation of initial and steady-state gatifloxacin pharmacokinetics and dose in pulmonary tuberculosis patients by using Monte Carlo simulations
%D 2013
%L PAR00010835
%G ENG
%J Antimicrobial Agents and Chemotherapy
%@ 0066-4804
%M ISI:000323285500009
%N 9
%P 4164-4171
%R 10.1128/aac.00479-13
%U https://www.documentation.ird.fr/hor/PAR00010835
%> https://www.documentation.ird.fr/intranet/publi/2024-04/010089857.pdf
%V 57
%W Horizon (IRD)
%X A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of >= 125 for the area under the concentration time curve to infinity (AUC(0-infinity)) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC(0-infinity) of 41.2 mu g.h/ml decreased on average by 14.3% (90% confidence interval [CI], -90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of >= 125 only when the MIC was <0.125 mu g/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.)
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