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

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.

HSP90alpha, HSP90beta, and p53 expression following in vitro hyperthermia exposure in gestation day 10 rat embryos.

The studies presented here are aimed at understanding the expression of p53, HSP90alpha, and HSP90beta in gestation day (GD) 10 CD rat embryos. GD 10 rat embryos were exposed in vitro to 37 degrees C or 42 degrees C for 15 min, then cultured at 37 degrees C for 0.5, 1, 3, or 5 h. Immunohistochemistry was performed on formalin-fixed, paraffin embedded, sectioned embryos for p53, HSP90alpha, or HSP90beta expression. p53 expression was minimal in control embryos but was induced with heat exposure. Maximum expression of p53 was observed in rostral tissues, e.g., the optic vesicle, rostral neuroepithelium, and mature (rostral) somites 3 and 5 h after heat exposure. Expression of p53 in the caudal region, such as in mid and caudal neuroepithelium, immature (caudal) somites, and presomitic mesoderm, was moderate compared to rostral areas. No p53 expression was observed in the heart under any condition. The rostral-caudal gradient of p53 expression was not observed for HSP90alpha expression. HSP90alpha was induced in heat-exposed embryos beginning at 1 h, predominantly in neural tube and optic vesicle. Moderate but increased expression was observed in the somites of heat-exposed embryos at 3 and 5 h. Expression of p53 was primarily nuclear while HSP90alpha expression was mostly cytoplasmic. No clear association was observed between heat-induced HSP90alpha and p53 expression. HSP90beta was expressed extensively in control and heat-exposed embryos. Results indicate that heat induces p53 and HSP90alpha expression, but not HSP90beta expression, and that HSP90alpha induction is not likely to be involved in p53 regulation in mammalian embryos.