Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model

Jiang Xiaoquan; Wang Guopeng; Miao Feng; Shi Lu; Sun Wenyan; Liu Yang

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Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model

Jiang Xiaoquan, Wang Guopeng, Miao Feng, Shi Lu, Sun Wenyan, Liu Yang

Published in Asia-Pacific Journal of Pharmaceutical Sciences (Volume 1, Issue 1)

Received: 31 October 2018 Accepted: 12 December 2018 Published: 1 February 2019

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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 C_max, AUC_0-inf and AUCAUC_0-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]/K_i value of inhibitors and the changes of the exposure to saxagliptin into account.

Published in	Asia-Pacific Journal of Pharmaceutical Sciences (Volume 1, Issue 1)
Page(s)	6-13
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Saxagliptin, Ketoconazole, Delavirdine, Physiologically Based Pharmacokinetic Model, Dynamic Drug-Drug Interactions Model

References

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APA Style

Jiang Xiaoquan, Wang Guopeng, Miao Feng, Shi Lu, Sun Wenyan, et al. (2019). 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, 1(1), 6-13.

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ACS Style

Jiang Xiaoquan; Wang Guopeng; Miao Feng; Shi Lu; Sun Wenyan, et al. Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model. Asia-Pac. J. Pharm. Sci. 2019, 1(1), 6-13.

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AMA Style

Jiang Xiaoquan, Wang Guopeng, Miao Feng, Shi Lu, Sun Wenyan, et al. Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model. Asia-Pac J Pharm Sci. 2019;1(1):6-13.

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@article{10034750,
  author = {Jiang Xiaoquan and Wang Guopeng and Miao Feng and Shi Lu and Sun Wenyan and Liu Yang},
  title = {Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model},
  journal = {Asia-Pacific Journal of Pharmaceutical Sciences},
  volume = {1},
  number = {1},
  pages = {6-13},
  url = {https://www.sciencepublishinggroup.com/article/10034750},
  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.},
 year = {2019}
}

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TY  - JOUR
T1  - Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model
AU  - Jiang Xiaoquan
AU  - Wang Guopeng
AU  - Miao Feng
AU  - Shi Lu
AU  - Sun Wenyan
AU  - Liu Yang
Y1  - 2019/02/01
PY  - 2019
T2  - Asia-Pacific Journal of Pharmaceutical Sciences
JF  - Asia-Pacific Journal of Pharmaceutical Sciences
JO  - Asia-Pacific Journal of Pharmaceutical Sciences
SP  - 6
EP  - 13
PB  - Science Publishing Group
UR  - http://www.sciencepg.com/article/10034750
AB  - 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.
VL  - 1
IS  - 1
ER  -

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Author Information

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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Plain Text BibTeX RIS

APA Style

Jiang Xiaoquan, Wang Guopeng, Miao Feng, Shi Lu, Sun Wenyan, et al. (2019). 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, 1(1), 6-13.

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ACS Style

Jiang Xiaoquan; Wang Guopeng; Miao Feng; Shi Lu; Sun Wenyan, et al. Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model. Asia-Pac. J. Pharm. Sci. 2019, 1(1), 6-13.

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AMA Style

Jiang Xiaoquan, Wang Guopeng, Miao Feng, Shi Lu, Sun Wenyan, et al. Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model. Asia-Pac J Pharm Sci. 2019;1(1):6-13.

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@article{10034750,
  author = {Jiang Xiaoquan and Wang Guopeng and Miao Feng and Shi Lu and Sun Wenyan and Liu Yang},
  title = {Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model},
  journal = {Asia-Pacific Journal of Pharmaceutical Sciences},
  volume = {1},
  number = {1},
  pages = {6-13},
  url = {https://www.sciencepublishinggroup.com/article/10034750},
  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.},
 year = {2019}
}

Copy | Download

TY  - JOUR
T1  - Predicting the Effect of Two Different Kinds of CYP3A4 Inhibitors on the Pharmacokinetic Characteristics of Saxagliptin Using Physiologically Based Pharmacokinetic Model
AU  - Jiang Xiaoquan
AU  - Wang Guopeng
AU  - Miao Feng
AU  - Shi Lu
AU  - Sun Wenyan
AU  - Liu Yang
Y1  - 2019/02/01
PY  - 2019
T2  - Asia-Pacific Journal of Pharmaceutical Sciences
JF  - Asia-Pacific Journal of Pharmaceutical Sciences
JO  - Asia-Pacific Journal of Pharmaceutical Sciences
SP  - 6
EP  - 13
PB  - Science Publishing Group
UR  - http://www.sciencepg.com/article/10034750
AB  - 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.
VL  - 1
IS  - 1
ER  -

Copy | Download