Physiologically-based pharmacokinetic modeling to evaluate in vitro-to-in vivo extrapolation for intestinal P-glycoprotein inhibition.

ABSTRACT: As one of the key components in model-informed drug discovery and development, physiologically-based pharmacokinetic (PBPK) modeling linked with in vitro-to-in vivo extrapolation (IVIVE) is widely applied to quantitatively predict drug-drug interactions (DDIs) on drug-metabolizing enzymes and transporters. This study aimed to investigate an IVIVE for intestinal P-glycoprotein (Pgp, ABCB1)-mediated DDIs among three Pgp substrates, digoxin, dabigatran etexilate, and quinidine, and two Pgp inhibitors, itraconazole and verapamil, via PBPK modeling. For Pgp substrates, assuming unbound Michaelis-Menten constant (K_m ) to be intrinsic, in vitro-to-in vivo scaling factors for maximal Pgp-mediated efflux rate (J_max ) were optimized based on the clinically observed results with

SUBMITTER: Yamazaki S 

PROVIDER: S-EPMC8752109 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature