Inter-study variability of preclinical in vivo safety studies and translational exposure-QTc relationships--a PKPD meta-analysis
| Autor: | V, Gotta, F, Cools, K, van Ammel, D J, Gallacher, S A G, Visser, F, Sannajust, P, Morissette, M, Danhof, P H, van der Graaf |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Sulfonamides Dose-Response Relationship Drug Moxifloxacin Sotalol Drug Evaluation Preclinical Reproducibility of Results Arrhythmias Cardiac Research Papers Translational Research Biomedical Long QT Syndrome Dogs Cardiac Conduction System Disease Heart Conduction System Heart Rate Phenethylamines Potassium Channel Blockers Animals Humans Telemetry Female Brugada Syndrome Fluoroquinolones |
| Zdroj: | British journal of pharmacology. 172(17) |
| ISSN: | 1476-5381 |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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