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

Jeffry A. Florian, Christoffer W. Tornøe, Richard Brundage, Ameeta Parekh, Christine E. Garnett

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128 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1152-1162
Number of pages11
JournalJournal of Clinical Pharmacology
Volume51
Issue number8
DOIs
StatePublished - Aug 1 2011

Keywords

  • ICH E14
  • Population pharmacokinetics
  • QT prolongation
  • exposure-response modeling
  • moxifloxacin
  • thorough QT studies

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