Quantitative pharmacokinetic-pharmacodynamic modeling to optimize targeted PI3K-AKT-mTOR oncology therapeutics development
department or school: Pharmaceutical Sciences, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Moein, Anita
issued: 2024-07-30T16:18:01Z
issued: 2024
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, and a master regulator for many cancer types. Massive efforts dedicated to the development of drugs targeting PI3K signaling, however, the number of approved inhibitors remains limited. Thesis objectives were to acquire a better understanding of the PI3K/AKT/mTOR pathway dynamic response by developing mechanistic preclinical and clinical pharmacokinetic (PK)-pharmacodynamic (PD) models. Conducted a retrospective assessment of the translational PK-PD modeling performance with apitolisib, a dual PI3K/mTOR inhibitor. Integrated PK-PD-Efficacy models developed for xenografts bearing human renal cell adenocarcinoma (RCC) and patients with solid tumors show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35% to 45% pAkt modulation is needed for tumor shrinkage in patients based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship, constant pAkt inhibition of 61% and 65% would be necessary to achieve tumor stasis in xenografts and patients, respectably. Developed a longitudinal exposure-tumor growth inhibition (TGI) model to characterize and compare everolimus (mTORC1 inhibitor) vs apitolisib’s (dual PI3K/mTORC1/2 inhibitor) ability to inhibit tumor growth, and quantitated each drug’s efficacy decay caused by emergence of tumor resistance over time in patients with metastatic-RCC. The estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Developed longitudinal TGI models to characterize tumor response in women with ER+/HER2- advanced/meta…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/88734
note: QUANTITATIVE PHARMACOKINETIC-PHARMACODYNAMIC MODELING TO OPTIMIZE TARGETED PI3K-AKT-MTOR ONCOLOGY THERAPEUTICS DEVELOPMENT by Anita Moein M.S., Pharmaceutical Sciences, University at Buffalo, 2014 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pharmaceutical Sciences) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2024 © Anita Moein, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Quantitative Pharmacokinetic-Pharmacodynamic Modeling to Optimize Targeted PI3K-AKT-mTOR Oncology Therapeutics Development Submitted by Anita Moein in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical Sciences Examining Committee: Dr. Harvey Wong, Associate Professor, Pharmaceutical Sciences, UBC Supervisor Dr. Matthew Wright, Executive Director, Drug Metabolism & Pharmacokinetics, Genentech Supervisory Committee Member Dr. Karla Williams, Associate Professor, Pharmaceutical Sciences, UBC University Examiner Dr. Anotida Madzvamuse, Professor, Mathematics, UBC University Examiner Additional Supervisory Committee Members: Dr. Thomas Chang, Professor and Associate Dean, Pharmaceutical Sciences, UBC Supervisory Committee Member Dr. Jin Y. Jin, Executive Director, Global Head of Modeling and Simulation, Genentech Supervisory Committee Member Dr. Shyh-Dar Li, Professor, Pharmaceutical Sciences, UBC Supervisory Committee Member iii Abstract Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, and a master regulator for many cancer types. Massive efforts dedicated to the development of drugs targeting PI3K signaling, however, the number of approved inhibitors remains limited. Thesis objectives were to acquire a better understanding o…
has type: Thesis/Dissertation
date issued: 2024-11
is shown at: 10.14288/1.0444850
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
contributor: Wong, Harvey
type: Text
identifier URI: http://hdl.handle.net/2429/88734