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The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model.
J Pharm Sci. 2020 May 26 [Online ahead of print]JP

Abstract

Sugar alcohols reduce oral drug bioavailability by osmotic effects, but the magnitude of these effects differs among different drugs. This study aimed to identify the drug-related critical attributes of osmotic effects and estimate the impact of a "practical" sugar alcohol dose on the pharmacokinetics of various molecules using modeling and simulation approaches. We developed a physiologically based biopharmaceutics model that considers the dose-dependent effects of sugar alcohols on the gastrointestinal physiology. The developed model captured the effects of sugar alcohols on ranitidine hydrochloride, metoprolol tartrate, theophylline, cimetidine, and lamivudine. Sensitivity analysis provided quantitative insights into the effects of sugar alcohols dependent on different drug permeability. In addition, our developed model indicated for the first time that a high systemic elimination rate is crucial for the reduction in maximum plasma concentration even for highly permeable drugs. Nonetheless, mannitol/sorbitol level of less than 400 mg had minor effects on the pharmacokinetics of the most sensitive drugs, indicating a provisional no-effect threshold dose. This mechanistic approach provides comprehensive estimation of osmotic effects on variety of drugs. Subsequently, these findings may invoke scientific discussion on the criteria for excipient changes in the context of biowaiver guidelines (e.g. biopharmaceutics classification system-based biowaiver).

Authors+Show Affiliations

Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka 532-0003, Japan.Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka 532-0003, Japan. Electronic address: kazuki.matsui@sawai.co.jp.Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka 532-0003, Japan.Sawai Pharmaceutical Co., Ltd., 5-2-30, Miyahara, Yodogawa-ku, Osaka 532-0003, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32470348

Citation

Yamane, Miki, et al. "The Provisional No-Effect Threshold of Sugar Alcohols On Oral Drug Absorption Estimated By Physiologically Based Biopharmaceutics Model." Journal of Pharmaceutical Sciences, 2020.
Yamane M, Matsui K, Sugihara M, et al. The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model. J Pharm Sci. 2020.
Yamane, M., Matsui, K., Sugihara, M., & Tokunaga, Y. (2020). The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2020.05.013
Yamane M, et al. The Provisional No-Effect Threshold of Sugar Alcohols On Oral Drug Absorption Estimated By Physiologically Based Biopharmaceutics Model. J Pharm Sci. 2020 May 26; PubMed PMID: 32470348.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Provisional No-Effect Threshold of Sugar Alcohols on Oral Drug Absorption Estimated by Physiologically Based Biopharmaceutics Model. AU - Yamane,Miki, AU - Matsui,Kazuki, AU - Sugihara,Masahisa, AU - Tokunaga,Yuji, Y1 - 2020/05/26/ PY - 2020/03/23/received PY - 2020/04/26/revised PY - 2020/05/15/accepted PY - 2020/5/30/pubmed PY - 2020/5/30/medline PY - 2020/5/30/entrez KW - Bioequivalence KW - Biopharmaceutics classification system (BCS) KW - Excipient(s) KW - In vitro/in vivo (IVIVC) correlation(s) KW - Osmotic pressure KW - Physiologically based pharmacokinetic (PBPK) modeling JF - Journal of pharmaceutical sciences JO - J Pharm Sci N2 - Sugar alcohols reduce oral drug bioavailability by osmotic effects, but the magnitude of these effects differs among different drugs. This study aimed to identify the drug-related critical attributes of osmotic effects and estimate the impact of a "practical" sugar alcohol dose on the pharmacokinetics of various molecules using modeling and simulation approaches. We developed a physiologically based biopharmaceutics model that considers the dose-dependent effects of sugar alcohols on the gastrointestinal physiology. The developed model captured the effects of sugar alcohols on ranitidine hydrochloride, metoprolol tartrate, theophylline, cimetidine, and lamivudine. Sensitivity analysis provided quantitative insights into the effects of sugar alcohols dependent on different drug permeability. In addition, our developed model indicated for the first time that a high systemic elimination rate is crucial for the reduction in maximum plasma concentration even for highly permeable drugs. Nonetheless, mannitol/sorbitol level of less than 400 mg had minor effects on the pharmacokinetics of the most sensitive drugs, indicating a provisional no-effect threshold dose. This mechanistic approach provides comprehensive estimation of osmotic effects on variety of drugs. Subsequently, these findings may invoke scientific discussion on the criteria for excipient changes in the context of biowaiver guidelines (e.g. biopharmaceutics classification system-based biowaiver). SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/32470348/The_Provisional_No-Effect_Threshold_of_Sugar_Alcohols_on_Oral_Drug_Absorption_Estimated_by_Physiologically_Based_Biopharmaceutics_Model L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(20)30262-8 DB - PRIME DP - Unbound Medicine ER -
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