Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays

Abstract:

Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies – radioligand-binding or automated electrophysiology – was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost.

 

Read more here: Morton MJ, Armstrong D, Abi Gerges N, Bridgland-Taylor M, Pollard CE, Bowes J, Valentin JP. (2014) Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays. Toxicol Appl Pharmacol. Sep 1;279(2):87-94.

By |2018-06-20T16:43:00+00:00September 20th, 2014|Ion Channels, Publications|Comments Off on Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays

About the Author:

Dr Michael Morton, PhD, Director and Cofounder, ApconiX, UK, an integrated toxicology and ion channel company that brings together a team of world-renowned nonclinical safety experts with over 400 years of drug discovery and development experience. Mike graduated from the University of Wolverhampton with a degree in Biomedical Sciences and then aspiration to work in hospital pathology. Having finished his Sandwich placement in Clinical Biochemistry at Sandwell Hospital and Mike subsequently gained a MSc in Clinical Biochemistry from the University of Manchester and carried out research into porphyrin metabolism. Moving to the University of Leeds, Mike completed his PhD in Pharmacology at researching adenosine receptor expression in the rat kidney . Mike was introduced to ion channels as a Post-Doc at Leeds and Yale University, patching with the likes of Fred Sigworth and Steve Hebert, then joined the Global Ion Channel Initiative at AstraZeneca. Mike worked at AstraZeneca for eight years before founding ApconiX with Professor Ruth Roberts and Dr Richard Knight. Mike has a serious passion for ion channels. And he’s very good at them . He is a serious scientist (with a serious sense of humour) who wants to make sure that every customer understands the consequences of the results he obtains and works with his colleagues to ensure a better decision is made on drug safety.