For this episode of Notes from the Lab we get into the scientific strategy of developing an anti-arrythmic drug — from scratch.

Bradycardia is generally resolved with atropine (first cardiac report circa 1867), and issues of aberrant conduction are addressed with beta blockers (Sir J. Black’s work in the 1960s earned him a Nobel prize in 1988 1 ). Sodium, calcium, and potassium channels are inhibited by a plethora of successful drugs like amiodarone (Labaz Labs, 1961), verapamil (Knoll AG, 1964), and dofetilide (Pfizer, 1999). But let’s ignore all of that, because this episode of Notes from the Lab pictures us developing a rhythm-normalizing drug.

Key to the development of new anti-arrhythmics is efficacy testing. In vitro tests include binding studies in which the ion channels are attached to a matrix, and the affinity of a drug candidate is measured in a 96-well-plate. Unfortunately, rapid and inexpensive binding assays give no indication of effect; will binding to the ion channel alter function, and how? The second level of investigation involves patch-clamp, in which the ionic channels expressed in cells are excited electrically, and the current they generate is recorded. Patch-clamp was automated in the late 1990s, but the automated and manual experiments remain medium-throughput, at best.

The unequivocal demonstration by patch-clamp that a cell can generate less current when its ion channels are blocked by a drug candidate is no proof that the effect will be felt across the entire heart, however: Verapamil, a potent calcium channel blocker, has little effect on the overall duration of the cardiac action potential (APD), because it also blocks potassium channels. The next step in developing an anti-arrhythmic therefore moves our drug candidate ex vivo, to an isolated heart preparation. APD and ECGs are measured that confirm the translation of the ionic channel block to a modification in APD and ECG intervals when an arrhythmia is elicited.

The last step in the anti-arrhythmic’s preclinical development is the small animal, either genetically modified or chemically or surgically induced into arrhythmia. Genetic mutations in the human population, such as LQT1, 2, or 3, have been associated with IKs, IKr, and Ina ion current abnormalities, and reproduced in animals. These animals, when instrumented with ECG electrodes, exhibit human-like arrhythmias which our drug candidate should eliminate when administered by its intended clinical route, at the intended clinical level of exposure.

Altogether, these in vitro, ex vivo, and in vivo models combine to build a pre-clinical portrait of our drug candidate which will predict its efficacy and ensure the safety of the volunteers and patients involved in the next phase of development: clinical trials.

References :

1. Stapleton MP. Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology. Tex Heart Inst J. 1997; 24(4):336-42.