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Interpretation
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
Overall, the interpretation of safety pharmacology data has to take all the available data into account. For assessment of the risk of QT prolongation in man, the data from in silico models, in vitro hERG channel assays, and studies using telemetric measurements from dogs together with blood concentrations necessary for therapeutic effect should be considered (Pollard et al. 2010). As an additional complexity, it has emerged that (Abi-Gerges et al. 2011) that the hERG channel consists of at least two subunits, which confer different sensitivities for different drugs. For example, fluoxetine was more potent at blocking hERG 1a/1b than 1a channels, while E-4031 showed the reverse.
The roles of human induced pluripotent stem cell-derived cardiomyocytes in drug discovery: managing in vitro safety study expectations
Published in Expert Opinion on Drug Discovery, 2020
Defining inclusion criteria for hiPSC-CMs using baseline characteristics and drug responses will be key in promoting the adoption of any model. In the HESI CiPA Pilot study to test for delayed repolarization with two hiPSC-CM cell lines, criteria for inclusion of sites were based on demonstrated sensitivity to IKr block (20% prolongation of repolarization with the specific blocking agent E-4031) and L-type calcium current block (20% shortening with the specific blocking agent nifedipine) [46]. These functional inclusion criteria resulted in 44% of sites being excluded in the final analysis. While this value may seem high (for example, compared to typical inclusion rates for mammalian ex vivo preparations) it is consistent with the greater potential for variability possible with different cell culture conditions and protocols used to generate hiPSC-CMs compared to stricter physiologic limits imposed by donor animals providing cardiac samples.