Repolarization assays

Martin, R.L., McDermott, J.S., Salmen, H.J., Palmatier, J., Cox, B.F., and Gintant, G.A., The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization influence of multi-channel block, /. Cardiovasc. Pharmacol, 43, 369-379, 2004. 

In the event of positive signals in both of the ion channel and in vivo assays, the repolarization assay is optional. If either or both the ion channel and in vivo QT assays yield a negative result, the repolarization assay should generally be performed. In some cases of negative or equivocal results in the in vivo QT assay, certain in vivo alternatives to the repolarization assay might be acceptable substitutes. 

While APD/repolarization assays are suggested as one approach to explore the risk for delayed repolarization (ICH S7B guidance), they are generally not widely used at present, likely due to the ease of use (and interpretation) of hERG current assays conpared to AP/repolarization studies in supporting regulatory submission, lack of accepted industry best-standard/practices for APD/repolarization assays, as well as potentially important differences in ventricular repolarization across species (vs. humans). For exanple, it is well established that I,j/hERG plays a prominent role in... 

Wallis, R.M. (2010) Integrated risk assessment and predictive value to humans of non-clinical repolarization assays. Br. J. Pharmacol. 159,115-121. 

Thertulien R, Manikhas GM, Dirix LY et al (2012) Effect of trabectedin on the QT interval in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol 69 341-350 TrepakovaES, Koerner J, Pettit SD, Valentin JR HESl Pro-Arrhythmia Committee (2009) A HESI consortium approach to assess the human predictive value of non-chnical repolarization assays. J Pharmacol Toxicol Methods 60 45-50... 

Fig. 2 An early version of the ICH S7B testing strategy, Step 2 circulated for comment included an evaluation of the action potential duration (repolarization assay) as a primary test with regard to assessing risk. This assay was moved to a secondary role by the time of the Step 2 revision to the draft guidance document...

Among these initiatives, the project of the HESI Cardiovascular Safety Subcommittee represented an analysis of the largest database among the different consortia, a survey of 150 molecules studied in the clinic for QT prolongation (Koemer et al. 2013). This initiative is comparing the concordance between preclinical cardiac repolarization assays and the results from the TQT study data were collected from INDs and NDAs submitted to the FDA between the periods of March 2006 and July 2012. Due to the proprietary namre of these datasets, the FDA populated the spreadsheets with the data and carried out a quality control and statistical analysis based on a methodology that was devised by the subcommittee in advance of the collection of data. The summary results of this analysis of 150 compounds has been presented at conferences and is due for publication in 2015 (Koemer et al. 2013). 

Trepakova ES, Koemer J, Pettit SD, Valoitm JP (2009) A HESI consortium approach to assess the human predictive value of nrm-clmical repolarization assays. J Pharmacol Toxicol Methods 60 45-50... 

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