Prediction Accuracy of Mechanism-Based Oral Absorption Model for Dogs

Akiyama, Yoshiyuki; Kimoto, Tetsuo; Mukumoto, Hanae; Miyake, Shuji; Ito, Shigeaki; Taniguchi, Tetsuo; Nomura, Yukihiro; Matsumura, Naoya; Fujita, Takuya; Sugano, Kiyohiko

doi:10.1016/j.xphs.2019.03.015

Cited by 16 publications

(22 citation statements)

References 56 publications

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“…Appropriate Fa SI prediction is the prerequisite for predicting the Fa values of free weak base drugs. As mentioned in the introduction, prior to the present study, the GUT framework has been validated for predicting Fa SI in humans and dogs [ 34 , 35 ]. In these studies, neutral and free weak acid drugs were mainly used because the Fa values of these drugs are little affected by gastric dissolution (Fa ≈ Fa SI ).…”

Section: Resultsmentioning

confidence: 99%

“…The gastric pH value after the administration of PPI or H 2 blockers was set to pH 6.0 for both humans and dogs [ 60 , 61 ]. The small intestinal pH values in fasted and fed dogs were set to be 7.0 and 6.0, respectively [ 34 , 62 ]. The other physiological parameters of the small intestine were the same as used in the previous studies [ 34 , 36 ].…”

Section: Theorymentioning

confidence: 99%

“…The small intestinal pH values in fasted and fed dogs were set to be 7.0 and 6.0, respectively [ 34 , 62 ]. The other physiological parameters of the small intestine were the same as used in the previous studies [ 34 , 36 ].…”

Section: Theorymentioning

confidence: 99%

“…Previously, the GUT framework has been systematically validated for neutral and acidic drugs by the consortium of biopharmaceutical tools (CoBiTo) in Japan [ 34 , 35 ]. The model equations and physiological parameters of the GUT framework have been fully disclosed and well documented in the literature [ 5 , 34 , 35 , 36 ]. In this study, a simple approximate analytical solution that describes the gastric dissolution processes of free weak base drugs was introduced to the GUT framework.…”

Section: Introductionmentioning

confidence: 99%

“…The gastrointestinal unified theoretical framework (the GUT framework) was employed as a simple and transparent model. Previously, the GUT framework has been systematically validated for neutral and acidic drugs by the consortium of biopharmaceutical tools (CoBiTo) in Japan [34,35]. The model equations and physiological parameters of the GUT framework have been fully disclosed and well documented in the literature [5,[34][35][36].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Resultsmentioning

confidence: 99%