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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
: Kambayashi, A.; Dressman, J.B.


Journal of pharmaceutical sciences 108 (2019), Nr.1, S.584-591
ISSN: 0022-3549
ISSN: 1520-6017
Fraunhofer IME ()

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.