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A novel in silico method to predict drug PK profile in human and its application to build the PBPK model of Hydroxychloroquine for COVID-19 treatment

Zhai, Jingchen (2021) A novel in silico method to predict drug PK profile in human and its application to build the PBPK model of Hydroxychloroquine for COVID-19 treatment. Master's Thesis, University of Pittsburgh. (Unpublished)

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The first part of this study is to develop a novel protocol to predict the pharmacokinetic profiles of a target drug based on the Physiologically based pharmacokinetic (PBPK) model of a structurally similar template drug by combining predictions from two software for PBPK modeling, the SimCYP simulator and ADMET Predictor. Thirteen drug pairs with Tanimoto similarity scores (TS) no less than 0.5 were studied. Three versions (V1, V2 and V3) of models using different predicted parameters for the target drug were constructed by replacing the corresponding parameters of the template drug step by step with those predicted by ADME Predictor for the target drug. Normalized Root Mean Square Error (NRMSE) was introduced for the evaluation of the model performance. Overall, for Group I drug pairs (TS ≤ 0.7), V2 and V3 perform better than V1 in terms of NRMSE; for Group II drug pairs (0.7 < TS ≤ 0.9), V3 outperforms the V1 and V2 versions. For the two drug pairs belong to Group III (TS > 0.9), V2 outperforms V1 and V3, suggesting more unnecessary replacement can lower the performance of PBPK models. We also investigated how the prediction accuracy of ADMET Predictor as well as its collaboration with SimCYP influence the quality of PBPK models constructed using SimCYP.
Hydroxychloroquine (HCQ) has been proposed as a promising treatment for COVID-19. To study the optimum dosing regimens for HCQ on COVID-19 that can balance its therapeutic efficacy and cardiac side-effect, we constructed a PBPK model for HCQ based on the method we proposed above and deducted the therapeutic window for COVID-19. To enable drug plasma concentration to reach the treatment level at the beginning of the treatment, we proposed to administrate HCQ either 600 mg BID or 800 mg BID first. Also, the maintaining dose of 400 mg BID or 200 mg TID in the following treatment is found necessary to maintain the drug plasma level until the 7th day. Drug concentrations in the heart and lung were also deducted to reflect dosing efficacy and to avoid the potential risk of cardiotoxicity. Reduced dosing regimens have also been proposed for the elderly and the renal impairment population.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhai, Jingchenjiz183@pitt.edujiz1830000-0003-2691-8867
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNolin,
Thesis AdvisorJunmei,
Committee MemberLirong,
Committee MemberXiangqun,
Date: 15 April 2021
Date Type: Publication
Defense Date: 26 March 2021
Approval Date: 15 April 2021
Submission Date: 5 April 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 77
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: PBPK modeling, Hydroxychloroquine, SimCYP simulation, ADEMT Predictor, parameter estimation, COVID-19
Date Deposited: 15 Apr 2021 13:01
Last Modified: 15 Apr 2023 05:15


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