Safety pharmacology in 2014: New focus on non-cardiac methods and models

Early Drug Discovery Prediction of Proarrhythmia Potential and Its Covariates

“…Currently, there are efforts to develop a Comprehensive In vitro Proarrhythmia Assay (CIPA) that aims to modify and modernize current non-clinical, “hERG-centric” cardiac safety screening efforts ( 2 , 13 , 14 ). Current alternative screening models and methods under consideration for the CIPA initiative include stem cells in which hERG (Kv11.1; I Kr current) as well as other cardiac ion channels such as the fast sodium (Nav1.5; I Na current) channel, persistent sodium channel ( I Nasus ), calcium (Cav1.2; I Ca current) channel as well as potassium channels such as the inward rectifier (Kir2.1-2.4; I K1 current), and slow delayed rectifying (Kv7.1; I Ks current) channel can be assessed in totality ( 15 ). Rather than examining human ion channel isoforms heterogeneously expressed in cell lines (such as CHO or HEK) as is current practice in drug safety, there is ongoing investigation of the applicability of human-induced pluripotent stem cells ( 16 ).…”

“…An inevitable component of this new paradigm is in silico methods which should became a vital element of cardiac safety testing. These include various approaches, starting from screening methods (QSAR-based models), up to the utilization of the biophysically detailed cardiac myocyte models ( 15 , 70 ). The latter techniques vary with regard of the level of complexity of the mathematical description of the cardiac physiology at the ion channel (Hodgkin-Huxley or Markovian notation) and cell level (single cell up to the three-dimensional heart structure) ( 71 , 72 ).…”

The shifting landscape of safety pharmacology in 2015

“…Current alternative screening models and methods under consideration by the safety pharmacology and regulatory communities for the CIPA initiative include human stem cells in which hERG (I Kr ) as well as other cardiac ion currents such as the fast inward sodium (I Na ), calcium (I CaL ) and additional potassium currents (I K1 and I Ks ) can be assessed in totality (Pugsley, Authier, & Curtis, 2008;Pugsley, Dalton, Authier, & Curtis, 2014). Thus, rather than examining drug effects on heterogeneously expressed human ion channel isoforms in HEK or CHO cell lines (as is current practice) to characterize drug safety, the safety pharmacology and scientific community is investigating applicability of human induced pluripotent stem cells (Peng, Lacerda, Kirsch, Brown, & Bruening-Wright, 2010).…”

Principles of Safety Pharmacology

“…Current alternative screening models and methods under consideration by the SP and regulatory communities for the CIPA initiative include stem cells in which hERG (I Kr ) as well as other cardiac ion channels such as sodium (SCN5A), calcium (Cav1.2) and some potassium channels (I K1 and I Ks ) can be assessed in totality (Pugsley et al 2014). Rather than examining human ion channel isoforms heterogeneously expressed in cell lines (such as CHO or HEK) as is current practice in drug safety or, on the rare occasion, actually using isolated human cardiac myocytes, the community is investigating applicability of human-induced pluripotent stem cells (Vidarsson et al 2010;Peng et al 2010).…”