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Integrated TK–TD modeling for drug-induced concurrent tachycardia and QT changes in beagle dogs

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Abstract

Drug-induced cardiotoxicity, including tachycardia and QT prolongation, remains a major safety concern that needs to be identified and its risk mitigated in early stages of drug development. In the present study, an integrated toxicokinetic–toxicodynamic (TK–TD) modeling approach within a nonlinear mixed-effect modeling framework is applied to investigate concurrent abnormal heart rate and QT changes in three beagle dogs, using a Novartis internal compound (NVS001) as the case example. By accounting for saturable drug absorption, circadian rhythms, drug-effect tolerance, and nonlinear rate-dependency of QT interval, the dynamic TK–TD model captures the experimentally observed drug effects on heart rate and QT interval across a wide dosing range of NVS001 in beagle dogs. Further analyses reveal that the NVS001-induced QT prolongation observed in the low-dose groups is potentially caused by direct drug inhibition on the hERG channel, while the apparent QT shortening in the high-dose groups may be due to strong rate-dependency of QT at high heart rates. This study also suggests that the TK–TD model can be used to identify direct drug effects on the non-rate-dependent QT component by dissociating QT changes from tachycardia and deriving a new QT correction method. The integrated TK–TD model presented here may serve as a novel quantitative framework for evaluating drug-induced concurrent changes in heart rate and QT to potentially facilitate preclinical and clinical safety studies.

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Acknowledgements

The authors are grateful to generous support from Kaci Phizackerley in formulation preparation and from David Tully in project management.

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Authors and Affiliations

  1. Department of PK Sciences, Novartis Institutes for BioMedical Research, 1 Health Plaza, East Hanover, NJ, USA

    Fan Wu, Tycho Heimbach, Panos Hatsis & Handan He

  2. Department of Preclinical Safety, Novartis Institutes for BioMedical Research, 1 Health Plaza, East Hanover, NJ, USA

    Hai-Ming Tang & Raviprakash Dugyala

  3. Department of PK Sciences, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA, USA

    Qin Yue

  4. Department of Preclinical Safety, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA, USA

    Tao Wang

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  1. Fan Wu
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  2. Tycho Heimbach
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Correspondence to Fan Wu.

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All authors were full-time employees of Novartis and potentially owned stock in Novartis when work presented in this manuscript was conducted.

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Wu, F., Heimbach, T., Hatsis, P. et al. Integrated TK–TD modeling for drug-induced concurrent tachycardia and QT changes in beagle dogs. J Pharmacokinet Pharmacodyn 44, 449–462 (2017). https://doi.org/10.1007/s10928-017-9532-2

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  • DOI: https://doi.org/10.1007/s10928-017-9532-2

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