Evaluation of moxifloxacin in canine and non‐human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration‐QTc analysis

Figures

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  FIGURE 1. Time‐response and concentration‐QTc (C‐QTc) relationship evaluation of moxifloxacin‐induced QTc prolongation in conscious beagle dogs. Vehicle (◦) and moxifloxacin (10, 30, and 100 mg/kg) were administered at 0 h. The plots represent timepoint analysis of absolute QTcI (a) and baseline‐ and vehicle‐corrected QTcI effects (ΔΔQTcI) (b) following treatment. The moxifloxacin pharmacokinetic curve (c) and C‐QTc relationship for moxifloxacin (d) are also shown. Group sizes were eight (a/b) or four (c/d) and values are mean ± SD. *Indicates significance (p < 0.05) for control versus low dose. The # indicates significance (p < 0.05) for control versus mid dose. The $ indicates significance (p < 0.05) for control versus high dose (repeated measures analysis of covariance followed by Dunnett’s pairwise comparisons). For panel d, data were fitted by linear regression (solid line) and dotted lines represent 90% confidence interval of the model‐predicted mean ΔΔQTcI

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  FIGURE 2. Time‐response and concentration‐QTc (C‐QTc) relationship evaluation of moxifloxacin‐induced QTc prolongation in conscious non‐human primates (NHPs). Vehicle (◦) and moxifloxacin (30, 80, and 175 mg/kg) were administered at 0 h. The plots represent timepoint analysis of absolute QTcI (a) and baseline‐ and vehicle‐corrected QTcI effects (ΔΔQTcI) (b) following treatment. The moxifloxacin pharmacokinetic curve (c) and C‐QTc relationship for moxifloxacin (d) are also shown. Group sizes were eight (a/b) or four (c/d) and values are mean ± SD. *Indicates significance (p < 0.05) for control versus low dose. The # indicates significance (p < 0.05) for control versus mid dose. The $ indicates significance (p < 0.05) for control versus high dose (repeated measures analysis of covariance followed by Dunnett’s pairwise comparisons). For panel d, data were fitted by linear regression (solid line) and dotted lines represent 90% confidence interval of the model‐predicted mean ΔΔQTcI.

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  FIGURE 3. Comparison of unbound concentration‐QTc (C‐QTc) relationship following moxifloxacin administration in: dog (a) and non‐human primate (NHP) (b) models. Human reference values were adapted from a meta‐analysis of 20 thorough QT (TQT) studies. 40 Unbound concentrations were calculated using species specific plasma protein binding, as specified in the Methods section. Dog and NHP data were fitted by linear regression (solid line) and dotted lines represent 90% confidence interval CI) of the model‐predicted mean ΔΔQTcI. Human data is mean value, with error bars representing 90% CI

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  FIGURE 4. Correlation plots of ΔΔQTc values for timepoint analysis and concentration‐QTc (C‐QTc) modeling from human, dog, and non‐human primate (NHP) QTc assays. Human TQT data (adapted ref. 40; N = 18 studies; R = 0.7093, R 2 = 0.5031) are presented in panel a. Dog and NHP data are overlaid with human data (from panel a) in panel b. Each nonclinical data point represents mean data (n = 8 for timepoint analysis and n = 4 for concentration‐QTc) at maximum plasma concentration for each dose level, with error bars representing SD