Integrated TK-TD modeling for drug-induced concurrent tachycardia and QT changes in beagle dogs.
J Pharmacokinet Pharmacodyn
; 44(5): 449-462, 2017 Oct.
Article
em En
| MEDLINE
| ID: mdl-28643108
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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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Taquicardia
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Eletrocardiografia
/
Modelos Biológicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article