CiPA

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).

Schematic of the elements of the CiPA. Abbreviations: HT, high throughput; Manual, manual patch voltage clamp.
Schematic of the elements of the CiPA. Abbreviations: HT, high throughput; Manual, manual patch voltage clamp.

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
HCN2 pacemaker current
HCN4 pacemaker 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
Nav1.5 sodium 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”.