Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model
Asia-Pacific Journal of Pharmaceutical Sciences
Volume 1, Issue 1, March 2019, Pages: 6-13
Received: Oct. 31, 2018; Accepted: Dec. 12, 2018; Published: Feb. 1, 2019
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Authors
Jiang Xiaoquan, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
Wang Guopeng, Zhongcai Health Biological Technology Development Co. Ltd., Beijing, China
Miao Feng, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
Shi Lu, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
Sun Wenyan, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
Liu Yang, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Abstract
Objective: The study aimed to predict the effects of two different types of inhibitors on the pharmacokinetics of saxagliptin and evaluate the potential DDIs by establishing dynamic drug-drug interactions (DDIs) models between saxagliptin and ketoconazole (a competitive inhibitor of CYP3A4), or delavirdine (a time-dependent inhibitor of CYP3A4). Methods: The physicochemical properties parameter, biopharmaceutical parameter, enzyme-catalyzed reaction parameter of drug metabolism, and human physiological parameter of saxagliptin, ketoconazole and delavirdine were collected by published literatures and ADMET Predictor, to build and verify the PBPK models of these three drugs. Then, combined with the inhibition parameter of enzyme and enzyme degradation rate constant, dynamic DDIs models of ketoconazole and delavirdine were separately established so as to predict the varieties of the pharmacokinetics of saxagliptin. Results: The dynamic DDIs model between saxagliptin and ketoconazole showed that Cmax, AUC0-inf and AUCAUC0-t of saxagliptin rose by 79.2%, 147.8% and 147.8% respectively. Higher values of the three pharmacokinetic parameters of saxaliptin were found as well in the dynamic DDIs model between saxagliptin and delavirdine, with the increase of 39.6%, 75.4% and 75.3 % correspondingly. Conclusion: Both inhibitors have effect on the pharmacokinetics of saxagliptin. Time-dependent inhibition’s impact is greater as taking the [I]/Ki value of inhibitors and the changes of the exposure to saxagliptin into account.
Keywords
Saxagliptin, Ketoconazole, Delavirdine, Physiologically Based Pharmacokinetic Model, Dynamic Drug-Drug Interactions Model
To cite this article
Jiang Xiaoquan, Wang Guopeng, Miao Feng, Shi Lu, Sun Wenyan, Liu Yang, Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model, Asia-Pacific Journal of Pharmaceutical Sciences. Vol. 1, No. 1, 2019, pp. 6-13.
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This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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