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Translating QT interval prolongation from conscious dogs to humans

Dubois, VF; Smania, G; Yu, H; Graf, R; Chain, A; Danhof, M; Pasqua, OD; (2016) Translating QT interval prolongation from conscious dogs to humans. British Journal of Clinical Pharmacology , 83 (2) pp. 349-362. 10.1111/bcp.13123. Green open access

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Abstract

AIM: Despite screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of pro-arrhythmic activity using a comprehensive in vitro pro-arrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. Here we evaluate the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. METHODS: Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of 9 compounds with varying QT prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymised NCEs) were analysed. Mean slope estimates varied between -0.98 and 6.1 ms/μM in dogs and -10 and 90 ms/μM in humans, indicating a wide range of effects on QT interval. Linear regression techniques were then applied to characterise the correlation between the parameters across species. RESULTS: For compounds without a mixed ion channel block a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x, R(2)  = 0.989).These results show that per unit concentration the drug effect on QT interval in humans is 11.6 fold larger than in dogs. CONCLUSIONS: Together with information about the expected therapeutic exposure, the evidence of a correlation between the compounds-specific parameter in dogs and humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalisability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans.

Type: Article
Title: Translating QT interval prolongation from conscious dogs to humans
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bcp.13123
Publisher version: http://doi.org/10.1111/bcp.13123
Language: English
Additional information: © 2016 The British Pharmacological Society. This is the peer reviewed version of the following article: Dubois, VF; Smania, G; Yu, H; Graf, R; Chain, A; Danhof, M; Pasqua, OD; (2016) Translating QT interval prolongation from conscious dogs to humans. British Journal of Clinical Pharmacology 10.1111/bcp.13123, which has been published in final form at http://doi.org/10.1111/bcp.13123. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Keywords: PKPD modelling, QT interval prolongation, candidate screening, drug development, interspecies differences, predictive modelling, pro-arrhythmic effect
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1516573
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