Efficient simulation of clinical target response surfaces

24 Feb 2022

Daniel Lill, Anne Kümmel, Venelin Mitov, Daniel Kaschek, Nathalie Gobeau, Henning Schmidt, Jens Timmer

Clinical Pharmacology and Therapeutics

Doi: 10.1002/psp4.12779

Photo: Dtimiraos_iStock


Simulation of combination therapies is challenging due to computational complexity. Either a simple model is used to simulate the response for many combinations of concentration to generate a response surface but parameter variability and uncertainty are neglected and the concentrations are constant—the link to the doses to be administered is difficult to make—or a population pharmacokinetic/pharmacodynamic model is used to predict the response to combination therapy in a clinical trial taking into account the time-varying concentration profile, interindividual variability (IIV), and parameter uncertainty but simulations are limited to only a few selected doses. We devised new algorithms to efficiently search for the combination doses that achieve a predefined efficacy target while taking into account the IIV and parameter uncertainty. The result of this method is a response surface of confidence levels, indicating for all dose combinations the likelihood of reaching the specified efficacy target. We highlight the importance to simulate across a population rather than focus on an individual. Finally, we provide examples of potential applications, such as informing experimental design.

To read the full article please visit the American Society for Clinical Pharmacology and Therapeutics website.