Predicting the Changes in Oral Absorption of Weak Base Drugs Under Elevated Gastric pH Using an In Vitro–In Silico–In Vivo Approach: Case Examples—Dipyridamole, Prasugrel, and Nelfinavir

The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH-dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasu...

Full description

Saved in:
Bibliographic Details
Published in:Journal of pharmaceutical sciences 2019-01, Vol.108 (1), p.584-591
Main Authors: Kambayashi, Atsushi, Dressman, Jennifer B.
Format: Article
Language:English
Subjects:
Administration, Oral
Computer Simulation
Dipyridamole - pharmacokinetics
dissolution
drug-drug interaction
Gastric Emptying - physiology
Humans
Hydrogen-Ion Concentration
in silico modeling
Intestinal Absorption - physiology
Models, Biological
Nelfinavir - pharmacokinetics
oral absorption
Permeability - drug effects
pharmacokinetics
poorly water-soluble drugs
Prasugrel Hydrochloride - metabolism
precipitation
simulation
Solubility
Stomach - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH-dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasugrel, and nelfinavir were simulated and compared with pharmacokinetic data reported in humans with or without use of proton pump inhibitors or histamine H2 receptor antagonists. The in vitro dissolution and precipitation data for the weakly basic drugs in biorelevant media were obtained using paddle apparatus. An in silico prediction model based on the STELLA software was designed and simulations were conducted to predict the oral pharmacokinetic profiles of the 3 drugs under both usual (low) and elevated gastric pH conditions. The changes in oral absorption of dipyridamole and prasugrel in subjects with elevated gastric pH compared with those with low stomach pH were predicted well using the in vitro–in silico–in vivo approach. The proposed approach could become a powerful tool in the formulation development of poorly soluble weak base drugs.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2018.11.008