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

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

doi:10.3390/pharmaceutics12090844

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

Pharmaceutics. 2020 Sep 3;12(9):844. doi: 10.3390/pharmaceutics12090844.

Authors

Naoya Matsumura¹, Asami Ono², Yoshiyuki Akiyama³, Takuya Fujita⁴, Kiyohiko Sugano⁵

Affiliations

¹ Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
² Laboratory for Chemistry, Manufacturing, and Control, Pharmaceuticals Production & Technology Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-2321, Japan.
³ Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
⁴ Laboratory of Molecular Pharmacokinetics, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
⁵ Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan.

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 pK_a, 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.

Keywords: free base; gastric dissolution; modeling; oral absorption; permeability; solubility.