Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis

Abstract

Background and purpose: Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans.

Experimental approach: We derived typical ΔQTc predictions at therapeutic exposure (ΔQTcTHER ) with 95% confidence intervals (95%CI) for 3 Kv 11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2-6 studies including 10-32 dogs per compound) to derive meta-predictions of typical ΔQTcTHER . Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature.

Key results: The 95%CIs of study-predicted ΔQTcTHER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1-69%). Meta-ΔQTcTHER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline.

Conclusions and implications: Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical-clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.

Figure 1

Illustration of the workflow of this PKPD meta-analysis (fully illustrated for moxifloxacin but also applies equally well to dofetilide and sotalol). An ISV in ΔQTc_THER predictions was also calculated from all 14 preclinical studies. The main results are summarized in Figure 5.

Figure 2

Illustration of pooled study data and meta-model predictions (parameters: see Table 2011). Left: PK: plasma concentration over time. Drugs were mainly given orally, only moxifloxacin 12.04 mg·kg⁻¹ and dofetilide 25.1 and 110 μg·kg⁻¹ were given as i.v. infusion. Dots: measured plasma concentrations. Lines: typical concentration prediction from meta-model. Right: PK-PD: Individual QTc (upper panel; all individuals, correction was made for heart rate and circadian variation) and drug-induced QTc prolongation (ΔQTc, lower panel) over time after vehicle administration, ≈human equivalent dose and ≈3× human equivalent dose. Dots: observations. Lines: individual model predictions. For moxifloxacin, only one individual per study is represented in the lower panels.

Figure 3

PD: Observed and predicted PD relationships from meta-analyses (upper panel: moxifloxacin, mid panel: dofetilide, lower panel: sotalol). (A) Observed ΔQTc (dots) with 90%PI (dashed lines: 5th and 95th percentiles) and typical meta-prediction (solid black line: 50th percentile). (B) Model-predicted PD relationships of individual dogs (thin grey lines) with 90%PI (dashed lines) and typical meta-prediction (solid black line). (C) Typical PD predictions from each study (coloured lines) and 95%CI of the typical prediction from the meta-analysis (shaded curve). Dotted lines: human therapeutic interval.

Figure 4

Summary and comparison of PD relationships in dogs and humans within unbound human therapeutic concentration range (predicted ΔQTc_THER(LL) and ΔQTc_THER(UL), from both the presented PKPD analyses and literature review). Left: QTc prolongation in [ms] illustrated for moxifloxacin in detail (for dofetilide and sotalol: see Supporting Information Appendix S2). Red horizontal line: 10 ms prolongation. Right: Corresponding QTc prolongation from baseline in [%] summarized for all three drugs. Red horizontal line: 2.5% prolongation (corresponding to ≈10 ms in human and 6 ms in the conscious dog). Dots: the point size of predictions is illustrated relative to the number of individuals included in the studies (‘weight’). Lines: the lines connect the predictions from different studies. Shaded areas: 95%CI (from pooled dog studies, i.e. preclinical meta-analysis) and range of study predictions from clinical meta-analysis (Florian et al., 2011) respectively.

Figure 5

Summary of main findings. Consistency: % deviation of individual study predictions from meta-predictions at upper level of therapeutic exposure (ΔQTc_THER(UL); ΔQTc_THER(LL) is illustrated in Supporting Information Appendix S3). Error bars: 95%CI. Vertical shaded area: ±30% = overall mean ISV estimate. Translation: PD relationships in the conscious dog [shaded area: 95%CI of meta-predictions (dark grey) and 90%PI (light grey)] are overlapping with clinical QTc prolongation (thin lines) at the lower and upper levels of therapeutic exposure (dots; clinical meta-predictions are indicated with larger dots) when expressed as %QTc prolongation from baseline (%ΔQTc).