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Characterizing QT interval prolongation in early clinical development: a case study with methadone

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 nonclin...

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Autores principales: Dubois, Vincent F. S., Danhof, Meindert, Della Pasqua, Oscar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461648/
https://www.ncbi.nlm.nih.gov/pubmed/28596836
http://dx.doi.org/10.1002/prp2.284
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author Dubois, Vincent F. S.
Danhof, Meindert
Della Pasqua, Oscar
author_facet Dubois, Vincent F. S.
Danhof, Meindert
Della Pasqua, Oscar
author_sort Dubois, Vincent F. S.
collection PubMed
description 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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spelling pubmed-54616482017-06-08 Characterizing QT interval prolongation in early clinical development: a case study with methadone Dubois, Vincent F. S. Danhof, Meindert Della Pasqua, Oscar Pharmacol Res Perspect Original Articles 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. John Wiley and Sons Inc. 2017-01-24 /pmc/articles/PMC5461648/ /pubmed/28596836 http://dx.doi.org/10.1002/prp2.284 Text en © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Dubois, Vincent F. S.
Danhof, Meindert
Della Pasqua, Oscar
Characterizing QT interval prolongation in early clinical development: a case study with methadone
title Characterizing QT interval prolongation in early clinical development: a case study with methadone
title_full Characterizing QT interval prolongation in early clinical development: a case study with methadone
title_fullStr Characterizing QT interval prolongation in early clinical development: a case study with methadone
title_full_unstemmed Characterizing QT interval prolongation in early clinical development: a case study with methadone
title_short Characterizing QT interval prolongation in early clinical development: a case study with methadone
title_sort characterizing qt interval prolongation in early clinical development: a case study with methadone
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461648/
https://www.ncbi.nlm.nih.gov/pubmed/28596836
http://dx.doi.org/10.1002/prp2.284
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