Project Dontabhaktuni - Method of Averaging Applied to PK/PD Modeling" Dr. Adrian Dunne - April 2021

Abstract:
The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MoA) in the appropriate circumstances. The MoA gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.e. repeats its values in regular intervals) and the rate of change of the PD response is such that it is approximately constant over a single period of the PK profile. This presentation explains the basis of the MoA by means of a simple mathematical derivation. The NONMEM® implementation of the MoA using the abbreviated FORTRAN function FUNCA is described and explained. The application of the MoA is illustrated by means of an example involving changes in glycated hemoglobin (HbA1c%) following administration of canagliflozin, a selective sodium glucose co transporter 2 (SGLT2) inhibitor. The PK/PD model applied to these data is fitted with NONMEM® using both the MoA and the standard method using a numerical differential equation solver (NDES). Both methods give virtually identical results but the NDES method takes almost 8 hours to run both the estimation and covariance steps, whilst the MoA produces the same results in less than 30 seconds. An outline of the NONMEM® control stream and the FORTRAN code for the FUNCA function is presented.
Slide Deck:
https://drive.google.com/drive/folders/1YBTeMDonUHsEbvF9atoUgOZLNQhBLZb-?usp=sharing

Adrian Dunne PhD.
Dr. Dunne’s background is in statistics, mathematics and pharmacology and he has more than 35 years experience in pharmacometrics. He was an associate professor in the University of California, San Francisco where he worked with Lewis Sheiner and Stuart Beal. Adrian spent more than 30 years in the Statistics and Pharmacology departments at University College Dublin. He also spent 6 years working with Janssen Research & Development where he was a scientific director and research fellow in the Model Based Drug Development group of the Quantitative Sciences division. He has taught in US and European universities for more than thirty years. His training courses have been highly recommended and are always well subscribed.
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Project Dontabhaktuni is a non-profit organization created to support scientist and students from around the world. The goal of “Project Dontabhaktuni” is to create training and mentoring programs for students and scientists all over the world that need to overcome the challenges of drug development particularly in pharmacometrics, leading to expediting drug development, appropriate drug therapy, and better patient outcomes.
In 2019 we visited China and India and hosted workshops in Many universities and have over 300 scientists taken advantage of our workshops. In 2020 we are hosting Free online workshops and reached over 1200 scientists from around the world.

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