Population pharmacokinetic and concentration--QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies

• Published in: Journal of clinical pharmacology Vol. 51; no. 8; p. 1152
• Main Authors: Florian, Jeffry A, Tornøe, Christoffer W, Brundage, Richard, Parekh, Ameeta, Garnett, Christine E
• Format: Journal Article
• Language: English
• Published: England 01.08.2011
• Subjects: Administration, Oral; Adolescent; Adult; Aged; Animals; Anti-Infective Agents - administration & dosage; Anti-Infective Agents - adverse effects; Anti-Infective Agents - blood; Anti-Infective Agents - pharmacokinetics; Aza Compounds - administration & dosage; Aza Compounds - adverse effects; Aza Compounds - blood; Aza Compounds - pharmacokinetics; Clinical Trials as Topic; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - adverse effects; Delayed-Action Preparations - pharmacokinetics; Drugs, Investigational - administration & dosage; Drugs, Investigational - adverse effects; Drugs, Investigational - analysis; Drugs, Investigational - pharmacokinetics; Electrocardiography - drug effects; Female; Fluoroquinolones; Humans; Intestinal Absorption; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Quinolines - administration & dosage; Quinolines - adverse effects; Quinolines - blood; Quinolines - pharmacokinetics; United States; United States Food and Drug Administration; Young Adult; United States
• ISSN: 1552-4604
• DOI: 10.1177/0091270010381498

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.