title: Moxifloxacin population pharmacokinetics and model-based comparison of efficacy between moxifloxacin and ofloxacin in African patients.
abstract: Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC0-24) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC0-24/MIC ratios of ≥53 and ≥100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of ≥53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of ≥100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Simbarashe P
authors.initials: SP
authors.lastname: Zvada
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Sirgel
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chigutsa
authors.forename: Mark
authors.initials: M
authors.lastname: Hatherill
authors.forename: Salome
authors.initials: S
authors.lastname: Charalambous
authors.forename: Stanley
authors.initials: S
authors.lastname: Mungofa
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
authors.forename: Amina
authors.initials: A
authors.lastname: Jindani
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrison
authors.forename: Helen M
authors.initials: HM
authors.lastname: McIlleron
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000493:pharmacokinetics*; D005260:Female; D024841:Fluoroquinolones / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D000077266:Moxifloxacin; D015242:Ofloxacin / Q000493:pharmacokinetics*; D018088:Tuberculosis, Multidrug-Resistant; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D015242:Ofloxacin; D000077266:Moxifloxacin