AI Article Synopsis

  • This study explored the feasibility of using an oral formulation of docetaxel combined with encequidar (oDox+E) as an alternative to the traditional intravenous (IV) dosage in cancer treatment, aligning with FDA's Project Optimus for improved drug development.
  • A population pharmacokinetic model was created to analyze how different dosing regimens of oDox+E compared to IV docetaxel in terms of achieving effective plasma concentrations, with a focus on reaching a target attainment probability (PTA) of 80% or higher.
  • Results indicated that while single-dose regimens of oDox+E fell short of the 80% PTA threshold, two- and

Article Abstract

Unlabelled: The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency.

Methods:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision.

Results:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels.

Conclusion:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11254990PMC
http://dx.doi.org/10.1007/s10928-024-09913-yDOI Listing

Publication Analysis

Top Keywords

drug development
20
pharmacokinetic model
16
population pharmacokinetic
16
docetaxel
12
odox + e
12
standard care
12
dose regimens
12
model
9
oral docetaxel
8
docetaxel encequidar
8

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!