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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 (AUC0-∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC0-∞ of 41.2 μg · 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 μg/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.).

Original publication

DOI

10.1128/AAC.00479-13

Type

Journal

Antimicrobial Agents and Chemotherapy

Publication Date

09/2013

Volume

57

Pages

4164 - 4171

Addresses

Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

Keywords

Humans, Tuberculosis, Pulmonary, HIV Infections, Isoniazid, Pyrazinamide, Fluoroquinolones, Rifampin, Antitubercular Agents, Drug Therapy, Combination, Drug Administration Schedule, Area Under Curve, Monte Carlo Method, Drug Synergism, Adult, Female, Male, Drug Dosage Calculations, Coinfection