Related Experiment Video
Updated: Jun 27, 2025
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Retrospective Assessment of Translational Pharmacokinetic-Pharmacodynamic Modeling Performance: A Case Study with
Anita Moein1,2, Jin Y Jin2, Matthew R Wright2
1Faculty of Pharmaceutical Sciences, University of British Columbia, Office 5505, Pharmaceutical Sciences Building, Vancouver, BC, Canada.
Background And Objectives:
Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K-AKT-TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models.
Methods:
Integrated pharmacokinetic (PK)-pharmacodynamic (PD)-efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K-AKT-mTOR pathway, and tumor response.
Results:
Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35-45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients.
Conclusions:
These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development.
Trial Registry:
ClinicalTrials.gov NCT00854152 and NCT00854126.
Insights
Mechanistic models revealed that a minimum of 35-45% phosphorylated Akt (pAkt) inhibition is required for tumor shrinkage. Achieving tumor stasis for apitolisib requires sustained pAkt inhibition of 61-65% in preclinical models and patients.
Area of Science:
- Oncology
- Pharmacology
- Translational Research
Background:
- Oncology drug development faces challenges in clinical success rates.
- Mechanistic models are vital for understanding drug effects and designing clinical trials.
- The PI3K-AKT-mTOR pathway is a key target in cancer therapy.
Purpose of the Study:
- To develop integrated mechanistic models for apitolisib, a PI3K/mTOR inhibitor.
- To bridge preclinical findings to clinical outcomes for apitolisib.
- To understand PI3K-AKT-mTOR pathway modulation and its effect on tumor response.
Main Methods:
- Developed integrated pharmacokinetic-pharmacodynamic-efficacy models.
- Utilized xenografts and human patients (Phase 1 studies).
- Characterized the relationship between apitolisib exposure, pAkt biomarker modulation, and tumor response.
Main Results:
- A steep sigmoid relationship was observed between pAkt inhibition and tumor growth inhibition.
- A minimum of 35-45% pAkt modulation is needed for tumor shrinkage in patients and xenografts.
- Sustained pAkt inhibition of 61% (xenografts) and 65% (patients) is required for tumor stasis.
Conclusions:
- The study validates the translatability of preclinical data to clinical targets.
- Findings enhance preclinical dose-finding and optimization for accelerated drug development.
- Integrated mechanistic models improve the prediction of clinical efficacy for oncology drugs.
Related Concept Videos
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
A recent model describes pravastatin's hepatobiliary excretion,...
01:20Pharmacokinetic Models: Overview
There are three primary types of models: empirical, compartment, and physiological. Empirical models, with minimal...
01:12Analysis of Population Pharmacokinetic Data
01:26Pharmacokinetic Models: Comparison and Selection Criterion
Physiological models take a detailed approach by considering specific molecular processes. They can predict drug distribution, metabolism, and elimination changes, providing a comprehensive understanding of how drugs interact with the body.
01:06Model Approaches for Pharmacokinetic Data: Distributed Parameter Models
The distributed parameter models are specifically designed to account for variations and differences in some drug classes. This model is particularly useful for assessing regional concentrations of anticancer or...
01:14Model Approaches for Pharmacokinetic Data: Compartment Models
Two primary types of compartment models are recognized: mammillary and catenary. The more...