title: Evaluation of initial and steady-state gatifloxacin pharmacokinetics and dose in pulmonary tuberculosis patients by using monte carlo simulations.
abstract: 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.).
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Wynand
authors.initials: W
authors.lastname: Smythe
authors.forename: Corinne S
authors.initials: CS
authors.lastname: Merle
authors.forename: Roxana
authors.initials: R
authors.lastname: Rustomjee
authors.forename: Martin
authors.initials: M
authors.lastname: Gninafon
authors.forename: Mame Bocar
authors.initials: MB
authors.lastname: Lo
authors.forename: Oumou
authors.initials: O
authors.lastname: Bah-Sow
authors.forename: Piero L
authors.initials: PL
authors.lastname: Olliaro
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: John
authors.initials: J
authors.lastname: Horton
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D060085:Coinfection; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D024841:Fluoroquinolones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077734:Gatifloxacin; D015658:HIV Infections / Q000821:virology; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D009010:Monte Carlo Method; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D000077734:Gatifloxacin; D007538:Isoniazid; D012293:Rifampin