Pharmacokinetic/pharmacodynamic modeling can guide drug candidate optimization
department or school: Pharmaceutical Sciences, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Yu, Meng Ke
issued: 2020-07-31T07:00:00Z
issued: 2019
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Optimization of drug candidates involves modification of chemical structures in order to improve a compoundâs desirable properties. We aim to use pharmacokinetic/pharmacodynamics (PK/PD) modelling to prioritize alterations in drug properties such as potency, clearance, and free drug concentrations in order to reduce the predicted efficacious dose. We have used simple differential equations and simulation software to build simple direct effect models to explore how changes in these factors affects a) maintenance of drug levels above 50% inhibition of a biological target or b) maintenance a certain efficacious area under the curve (AUC). We have demonstrated that when the pharmacodynamic target was to maintain >50% inhibition of a biological target, decreasing clearance led to greater decreases in predicted efficacious dose compared to improvements in potency. Changes in free drug levels affects both potency and clearance. The overall effect on dose was dependent on whether the drug was a high, moderate, or low clearance drug. When the pharmacodynamics target was efficacious AUC, improvements in predicted efficacious dose changed linearly with improvements in clearance or potency. These results indicate that the choice of property to optimize depends on the pharmacodynamic endpoint. When target is an efficacious AUC, one can choose to improve either clearance or potency with similar effects in steady-state dose improvements. However, when the target is maintenance of a specific level of target inhibition, better gains in dose reduction can be made by improvement of clearance rather than potency. Our study also demonstrates that application of PK/PD modelling can guide compound optimization in a more rational manner.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/71151
note: PHARMACOKINETIC/PHARMACODYNAMIC MODELING CAN GUIDE DRUG CANDIDATE OPTIMIZATION by Meng Ke Yu B.Sc., The University of British Columbia, 2017 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmaceutical Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2019 © Meng Ke Yu, 2019 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis/dissertation entitled: Pharmacokinetic/pharmacodynamic modeling can guide drug candidate optimization submitted by Meng Ke Yu in partial fulfillment of the requirements for the degree of Master of Science in Pharmaceutical Sciences Examining Committee: Harvey Wong, Pharmaceutical Sciences Supervisor Thomas Chang, Pharmaceutical Sciences Supervisory Committee Member Shyh-Dar Li, Pharmaceutical Sciences Supervisory Committee Member Brent Page, Pharmaceutical Sciences Additional Examiner Additional Supervisory Committee Members: Colin Ross, Pharmaceutical Sciences Supervisory Committee Member Supervisory Committee Member iii Abstract Optimization of drug candidates involves modification of chemical structures in order to improve a compoundâs desirable properties. We aim to use pharmacokinetic/pharmacodynamics (PK/PD) modelling to prioritize alterations in drug properties such as potency, clearance, and free drug concentrations in order to reduce the predicted efficacious dose. We have used simple differential equations and simulation software to build simple direct effect models to explore how changes in these factors affects a) maintenance of drug levels above 50% inhibition of a biological target or b) maintenance a certain efficacious area under the curve (AUC). We have demonstrated that when the pharmacodynamic target was to maintain >50% inhibition of a biological target, decreasing clearance led to greater decreases in predicted e…
has type: Thesis/Dissertation
date issued: 2019-09
is shown at: 10.14288/1.0380219
language: eng
degree discipline: Pharmaceutical Sciences
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/71151