Predicting QRS and PR interval prolongations in humans using nonclinical data.

ABSTRACT:

Background and purpose

Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase.

Experimental approach

Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model.

Key results

Meaningful (10%) human QRS/PR effects correlated wi

SUBMITTER: Bergenholm L 

PROVIDER: S-EPMC5595766 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature