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.
MULTIFILE
OBJECTIVE: The aim of this study was to investigate whether dynamic balance, measured with the anterior component of the Star Excursion Balance Test (SEBT-ANT), is a risk factor for ankle injuries in physical education teacher education (PETE) students.DESIGN AND SETTING: A prospective monocentre study in first-year PETE students.PARTICIPANTS: A total of 196 subjects, of which 137 men (70%) and 59 women (30%).OUTCOME MEASURES: This study consisted of measures of the SEBT-ANT at baseline (September 2015) and an injury registration procedure during a follow-up period (September 2015-June 2016). The association between the SEBT-ANT score and subsequent ankle injury was analysed with generalised estimating equations analysis at the leg level.RESULTS: Men and women had an average SEBT-ANT score of, respectively, 65.1% and 67.7% of leg length. In 20 (15%) subjects, the first injured body site involved the ankle. Across all participants, a below average SEBT-ANT score was not associated with increased ankle injury odds (OR OR=2.43, 95% CI: 0.94 to 6.29, p=0.07). In men, a below average SEBT-ANT score indicated sevenfold increased odds for ankle injury (OR=7.06, 95% CI: 1.43 to 34.92, p=0.02). In women, this relationship was not significant (OR=0.72, 95% CI: 0.19 to 2.71, p=0.62).CONCLUSIONS: Below average normalised SEBT-ANT scores were associated with sevenfold likelihood for ankle injuries in men. In contrast, no relationship was found for the SEBT-ANT score and ankle injuries in woman. These results may provide directions for the implementation of screening tools, as part of an injury prevention programme, to identify male PETE students with an increased likelihood for ankle injuries.
