Compound attrition and drug development costs have increased considerably since the advent of the clinical Thorough QT studies, supporting the need to reconsider the current cardiovascular liability assessment strategy.
The Comprehensive In Vitro ProArrhythmia Assay (CiPA) represents a paradigm shift towards a more complete assessment of proarrhythmic risk rather than QT prolongation alone.
The CiPA approach includes evaluating drug effects on multiple cardiac ionic currents, then integrating the data into in silico modeling, and finally confirming the data through the use of human stem cell-derived cardiomyocytes (Sager et al, 2014).
The higher specificity of the CiPA strategy will produce less false positives than those based purely on functional hERG studies. According to Kramer et al, 2013, patch-clamp results on three ionic currents predict proarrhythmia better than hERG assessment alone. CiPA recognizes that hERG represents only one of multiple ion currents which define cardiac electrophysiology.
The CIPA strategy is based on patch-clamp assessment of inhibition on the following channels:
|Cardiac Ion Channels||Function|
|Cav1.2/β2/α2δ1||L-type calcium current|
|Cav3.2||T-type calcium current|
|hERG||delayed rectifier potassium current|
|Kir2.1||inward rectifier potassium current|
|Kir3.1/3.4||inward rectifier potassium current|
|Kir6.2/SUR2A||inward rectifier potassium current|
|Kv1.5||delayed rectifier potassium current|
|Kv4.3||transient outward potassium current|
|KvLQT1/minK||delayed rectifier potassium current|
Ahead of the regulatory acceptance of CIPA (planned for early 2016), it has become common practice to estimate cardiovascular liability from patch-clamp inhibition data involving INa, ICa-L, IKr (hERG), and ITo, as a “mini comprehensive in-vitro panel”.