Physiologically based pharmacokinetic modelling and in vivo [I]/K(i) accurately predict P-glycoprotein-mediated drug-drug interactions with dabigatran etexilate.

ABSTRACT:

Background and purpose

In vitro inhibitory potency (Ki )-based predictions of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) are hampered by the substantial variability in inhibitory potency. In this study, in vivo-based [I]/Ki values were used to predict the DDI risks of a P-gp substrate dabigatran etexilate (DABE) using physiologically based pharmacokinetic (PBPK) modelling.

Experimental approach

A baseline PBPK model was established with digoxin, a known P-gp substrate. The Km (P-gp transport) of digoxin in the baseline PBPK model was adjusted to Km (i) to fit the change of digoxin pharmacokinetics in the presence of a P-gp inhibitor. Then 'in vivo' [I]/Ki of this P-gp inhibitor was calculated using Km (i) /Km . Baseline PBPK model was developed for DABE, an

SUBMITTER: Zhao Y 

PROVIDER: S-EPMC3925042 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature