Prediction of plasma profiles of a weakly basic drug after administration of omeprazole using PBPK modeling

Abstract

Background: Oral medicines must release the drug appropriately in the GI tract in order to assure adequate and reproducible absorption. Disease states and co-administration of drugs may alter GI physiology and therefore the release profile of the drug. Acid-reducing agents (ARAs), especially proton pump inhibitors (PPIs), are frequently co-administered during various therapies. As orally administered drugs are frequently poorly soluble weak bases, PPI co-administration raises the risk of pH-induced drug-drug interactions (DDIs) and the potential for changes in the therapeutic outcome.

Methods: This research compared the dissolution data of a poorly soluble weakly basic drug ("PSWB 001") from capsules in standard fasted state biorelevant media (FaSSGF, FaSSIF V1 and FaSSIF V2), water and recently devised media representing gastric conditions under various levels of PPI co-administration. An in silico simulation model, based on Simcyp software, was developed to compare simulated plasma profiles with clinical data.

Results: PSWB 001 capsules showed rapid and complete dissolution in acidic conditions representing gastric fluids, whereas limited dissolution was observed in deionized water, media representing PPI co-administration and in two biorelevant media representing fluids in the upper small intestine. Buffer capacity and the presence of native surfactants were shown to be important factors in the in vitro dissolution of PSWB 001. The data from in vitro experiments were used in conjunction with the in silico simulation model, which correctly predicted the plasma profiles of PSWB 001 when administered without PPIs, as well as bracketing the PPI effect observed in vivo.

Conclusions: Recently developed biorelevant media representing gastric conditions under PPI therapy, combined with PBPK modeling, were able to bracket the observed plasma profiles of PSWB 001. These media may also be useful for predicting PPI effects for other poorly soluble, weakly basic drugs.

Keywords: Acid-reducing agent; Dissolution; Drug-drug interaction(s); Physiologically based pharmacokinetic (PBPK) modeling; Proton pump inhibitor; Weak base; pH.