Pharmacokinetic-pharmacodynamic modelling of drug-induced QTc interval prolongation in man: prediction from in vitro human ether-a-go-go-related gene binding and functional inhibition assays and conscious dog studies.

ABSTRACT:

Background and purpose

Functional measures of human ether-à-go-go-related gene (hERG; Kv 11.1) channel inhibition have been prioritized as an in vitro screening tool for candidate molecules. However, it is unclear how these results can be translated to humans. Here, we explore how data on drug binding and functional inhibition in vitro relate to QT prolongation in vivo. Using cisapride, sotalol and moxifloxacin as paradigm compounds, we assessed the relationship between drug concentrations, binding, functional measures and in vivo effects in preclinical species and humans.

Experimental approach

Pharmacokinetic-pharmacodynamic modelling was used to characterize the drug effects in hERG functional patch clamp, hERG radio-labelled dofetilide displacement experiments and QT inte

SUBMITTER: Dubois VF 

PROVIDER: S-EPMC5055135 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature