title: Reevaluation of moxifloxacin pharmacokinetics and their direct effect on the QT interval.
abstract: The objectives of this study were to investigate the population pharmacokinetics of moxifloxacin and their relationship with the observed QT interval as well as the effect of covariates in healthy subjects using nonlinear mixed-effects modeling. A pool of 4 thorough QT studies were used, representing 99 healthy subjects who received moxifloxacin. The data were modeled using Monolix. Moxifloxacin pharmacokinetics were ascribed a 2- compartment open model. The TRANSIT model provided a better description of the delay in absorption than did the LAG model. The most significant covariate was lean body mass (LBM). The population estimates for clearance and central volume of distribution were 10.0 L/h per 60 kg of LBM and 131 L per 60 kg of LBM, respectively. The effect of moxifloxacin on QT was investigated using a direct effect model. The SLOPE model, relating the QT increase as a linear function of concentration, provided a better description of the pharmacodynamic effect than did the Emax model. The unique covariate was gender for both baseline QT and individual heart rate correction factor. The pharmacokinetics of moxifloxacin were satisfactorily described by an open 2-compartmental model with linear elimination. The trigonometric equation with a direct and proportional concentration effect satisfactorily described the effect on QT.
authors.affiliation: Sanofi-Aventis R&D, Clinical and Exploratory Pharmacology, 1, Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. philippe.grosjean@sanofi-aventis.com
authors.forename: Philippe
authors.initials: P
authors.lastname: Grosjean
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001372:Aza Compounds / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D001823:Body Composition; D001835:Body Weight; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D011804:Quinolines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin