Prediction of the dose range for adverse neurological effects of amiodarone in patients from an in vitro toxicity test by in vitro-in vivo extrapolation.

ABSTRACT: Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro-in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration-effect relationship into in vivo effective human doses, using the calculated in vitro area under the c

SUBMITTER: Algharably EAE 

PROVIDER: S-EPMC8032623 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature