title: Population pharmacokinetic and concentration--QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies.
abstract: To increase our understanding of important subject characteristics and design variables affecting the performance of oral moxifloxacin in thorough QT studies, population pharmacokinetic and concentration-QTc models were developed by pooling data from 20 studies. A 1-compartment model with first-order elimination described the pharmacokinetics. Absorption delay was modeled using 8 transit compartments. Mean (95% confidence interval) values for oral clearance, apparent volume of distribution, the first-order absorption rate constant, and mean transit time were 11.7 (11.5-11.9) L/h, 147 (144-150) L, 1.9 (1.7-2.1) 1/h, and 0.3 (0.28-0.34) hours, respectively. Overencapsulating the moxifloxacin tablet increased mean transit time by 138% and delayed time to maximum concentration by 0.5 hours but had a minimal effect on overall exposure. Administration with food decreased absorption rate constant by 27%. Women had higher moxifloxacin exposure compared with men, which was explained by lower body weights. A linear model described the concentration-QTc relationship with a mean slope of 3.1 (2.8-3.3) milliseconds per µg/mL moxifloxacin. Mean slopes for individual studies ranged from 1.6 to 4.8 milliseconds per µg/mL. Hysteresis between moxifloxacin plasma concentrations and QTc was modest, and incorporating this delay did not result in a different slope (3.3 milliseconds per µg/mL). There were no differences in slope estimates between men and women or among race categories.
authors.affiliation: Division of Pharmacometrics, Office of Clinical Pharmacology, Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
authors.forename: Jeffry A
authors.initials: JA
authors.lastname: Florian
authors.forename: Christoffer W
authors.initials: CW
authors.lastname: Tornøe
authors.forename: Richard
authors.initials: R
authors.lastname: Brundage
authors.forename: Ameeta
authors.initials: A
authors.lastname: Parekh
authors.forename: Christine E
authors.initials: CE
authors.lastname: Garnett
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics*; D001372:Aza Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000032:analysis / Q000493:pharmacokinetics; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics*; D014481:United States; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D001372:Aza Compounds; D003692:Delayed-Action Preparations; D015507:Drugs, Investigational; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin