Overcoming Analytical Method Development Challenges: Analysis Of Nonclinical Dose Formulations From hERG Studies
July 17, 2014 @ 1:00 pm
The ICH S7B guidelines recommend in vitro assessment for for drug-induced prolongation fo the QT interval for most small molecule IND submissions. The hERG (human ether-a-go-go-related gene) channel is an inward rectifying potassium channel that controls the cardiac action potential repolarization. Drugs that inhibit the hERG channel have the potential to prolong the cardiac action potential and cause torsade de pointes. A board range of in vitro concentrations assessments on the hERG channel activity relative to the Cmax plasma levels will give an estimated safety margin for the liability for delayed ventricular repolarization.
Formulation analysis of the test article in study vehicles are needed to determine the concentration, uniformity, and stability of the formulation. For hERG studies, the vehicle is a physiological salt solution (PSS). Depending on the physicochemical characteristics of the test article in PSS can pose unique challenges in the areas of solubility, stability, and recovery from the formulation for analysis. All challenges require analytical expertise in method development and a methodical approach so that a suitable method can be developed and validated.