Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.
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Atrial fibrillation (AF) is the most common clinical tachyarrhythmia associated with significant morbidity and mortality and is expected to affect approximately 30 million North Americans and Europeans by 2050. AF is a persistent disease, caused by progressive, often age-related, derailment of proteostasis resulting in structural remodeling of the atrial cardiomyocytes. It has been widely acknowledged that the progressive nature of the disease hampers the effective functional conversion to sinus rhythm in patients and explains the limited effect of current drug therapies. Therefore, research is directed at preventing new-onset AF by limiting the development of substrates underlying AF promotion. Upstream therapy refers to the use of drugs that modify the atrial substrate- or target-specific mechanisms of AF, with the ultimate aim to prevent the occurrence (primary prevention) and recurrence of the arrhythmia following (spontaneous) conversion and to prevent the progression of AF (secondary prevention). Recently, we observed that heat shock protein (HSP)-inducing drugs, such as geranylgeranylacetone, prevent derailment of proteostasis and remodeling of cardiomyocytes and thereby attenuate the AF substrate in cellular, Drosophila melanogaster, and animal experimental models. Also, correlative data from human studies were consistent with a protective role of HSPs in preventing the progression from paroxysmal AF to permanent AF and in the recurrence of AF. In this review, we discuss novel HSP-inducing compounds as emerging therapeutics for the primary and secondary prevention of AF. © 2012 Elsevier Inc.
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