Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs.

Naoya Matsumura,Kiyohiko Sugano,Yoshiyuki Akiyama,Takuya Fujita,Asami Ono

doi:10.3390/pharmaceutics12090844

Naoya Matsumura, Kiyohiko Sugano + Show 3 more

Open Access

https://doi.org/10.3390/pharmaceutics12090844

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Abstract

In this study, we systematically evaluated “bottom-up” physiologically based oral absorption modeling, focusing on free weak base drugs. The gastrointestinal unified theoretical framework (the GUT framework) was employed as a simple and transparent model. The oral absorption of poorly soluble free weak base drugs is affected by gastric pH. Alternation of bulk and solid surface pH by dissolving drug substances was considered in the model. Simple physicochemical properties such as pKa, the intrinsic solubility, and the bile micelle partition coefficient were used as input parameters. The fraction of a dose absorbed (Fa) in vivo was obtained by reanalyzing the pharmacokinetic data in the literature (15 drugs, a total of 85 Fa data). The AUC ratio with/without a gastric acid-reducing agent (AUCr) was collected from the literature (22 data). When gastric dissolution was neglected, Fa was underestimated (absolute average fold error (AAFE) = 1.85, average fold error (AFE) = 0.64). By considering gastric dissolution, predictability was improved (AAFE = 1.40, AFE = 1.04). AUCr was also appropriately predicted (AAFE = 1.54, AFE = 1.04). The Fa values of several drugs were slightly overestimated (less than 1.7-fold), probably due to neglecting particle growth in the small intestine. This modeling strategy will be of great importance for drug discovery and development.

Highlights

Recent drug candidates show poor solubility in aqueous media [1]
The oral absorption of poorly soluble drugs is susceptible to various physiological conditions in the GI tract, such as gastric pH, intestinal pH, buffer capacity, bile micelle concentration, gastrointestinal transit time, and hydrodynamics [3,4,5]
Drug-drug interactions (DDI) with gastric acid-reducing agents (ARA), such as antacids, H2 blockers, and proton pump inhibitors, are of great clinical importance, as they could reduce the efficacy of a drug by interfering with gastric dissolution [6,7,8]

Summary

Introduction

Recent drug candidates show poor solubility in aqueous media [1]. It is important to accurately evaluate the oral absorption of a drug candidate at the preclinical stage and design a formulation suitable for clinical studies [2]. The oral absorption of poorly soluble drugs is susceptible to various physiological conditions in the GI tract, such as gastric pH, intestinal pH, buffer capacity, bile micelle concentration, gastrointestinal transit time, and hydrodynamics [3,4,5]. In the case of poorly soluble weak base drugs, gastric dissolution can have a marked impact on their oral absorption. Drug-drug interactions (DDI) with gastric acid-reducing agents (ARA), such as antacids, H2 blockers, and proton pump inhibitors, are of great clinical importance, as they could reduce the efficacy of a drug by interfering with gastric dissolution [6,7,8]. Elderly subjects tend to be achlorhydric [9,10]

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Discussion

Conclusion