Population Pharmacokinetic and Concentration-QTc Models for Moxifloxacin: Pooled Analysis of 20 Thorough QT Studies

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 mu g/mL moxifloxacin. Mean slopes for individual studies ranged from 1.6 to 4.8 milliseconds per mu g/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 mu g/mL). There were no differences in slope estimates between men and women or among race categories.