ArticlePharmacology research & perspectives2017
Characterizing QT interval prolongation in early clinical development: a case study with methadone.
Article in Pharmacology research & perspectives, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed, 2 citations in OpenAlex.
- An open-label, single-arm, dose-escalating concentration-QT study to investigate the cardiac effects and safety of paroxetine in healthy adults.British journal of clinical pharmacology · 2026Article
- Characterizing QT interval prolongation in early clinical development: a case study with methadone.Pharmacology research & perspectives · 2017Article
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Authors and funding
3 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of ≥5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug-specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical.
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