Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

Abstract

Aims: Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin.

Methods: Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration.

Results: A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans.

Conclusions: Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule.

Keywords: QTc interval prolongation; model-based drug development; pre-clinical studies; translational science.

Figure 1

Pharmacokinetic analysis of data in conscious dogs (left) and healthy volunteers (right). (A) cisapride: (upper panel) individual observed concentrations vs. time for a typical subject and (lower panel) observed population median concentrations vs. time; symbols depict different dose levels: ○ and ____ for 0.6 mg kg⁻¹, △ and – – – for 2 mg kg⁻¹, + and - - - for 6 mg kg⁻¹ in conscious dogs, and ○ and ____ for 10 mg, Δ and – – – for 20 mg, + and - - - for 40 mg, x and - – - – for 80 mg, ◊ and — — — for 120 mg in healthy subjects. (B) sotalol: (upper panels) individual predicted concentration vs. time, (middle panels) population predicted concentration vs. time and(lower panels) individual predicted vs. observed sotalol concentrations; symbols depict different dose levels: ○ and ____ for 4 mg kg⁻¹, △ and – – – for 8 mg kg⁻¹ in conscious dogs, and ○ and ____ for 160 mg in healthy subjects. (C) moxifloxacin: (upper panels) individual predicted concentration vs. time, (middle panels) population predicted concentration vs. time and (lower panels) individual predicted vs. observed concentrations; symbols depict different dose levels: ○ and ____ for 3 mg kg⁻¹, △ and – – – for 10 mg kg⁻¹, + and - - - for 30 mg kg⁻¹ in conscious dogs and ○ and ____ for 400 mg in healthy subject

Figure 2

Pharmacokinetic–pharmacodynamic relationship between QT_c interval and plasma concentrations for conscious dogs (left) and healthy subjects (right). The top panels depict the observed QT intervals vs. time stratified by dose, whilst the middle and lower panels show the observed QT intervals vs. population prediction stratified by dose and the observed vs. the predicted individual QT intervals, respectively. (A) cisapride; symbols depict different dose levels: ○ and ___ for placebo, △ and – – – for 0.6 mg kg⁻¹, + and - - - for 2 mg kg⁻¹, x and - – - – for 6 mg kg⁻¹ in conscious dogs, and ○ and ___ for placebo, △ and – – – for 10 mg, + and - - - for 20 mg, x and - – - – for 40 mg, ◊ and — — — for 80 mg, ▿ and - – - – for 120 mg in healthy subjects. (B) d,l-sotalol; symbols depict different dose levels: ○ and ___ for placebo, △ and – – – for 4 mg kg⁻¹, + and - - - for 8 mg kg⁻¹ in conscious dogs, and ○ and ___ for 160 mg in healthy subjects. (C) moxifloxacin; symbols depict different dose levels: ○ and ___ for pre-dose, △ and – – – for placebo, + and - - - for 3 mg kg⁻¹, x and - – - – for 10 mg, ◊ and — — — for 30 mg in conscious dogs, and ○ and ___ for 400 mg in healthy subjects. The lines represent the regression for the population prediction using the model parameters. Dots show the observed QT interval and the corresponding (predicted) individual concentration data

Figure 3

Goodness-of-fit plots showing model-predicted vs. observed QT_c interval (upper panel) and corresponding probability curves for QT_c interval prolongation ≥10 ms vs. the predicted plasma concentrations (lower panel) of cisapride (A), d,l-sotalol (B) and moxifloxacin (C). Black dots and dotted lines represent values for conscious dogs, grey dots and solid lines depict data in healthy subjects