Open AccessEfficient simulation of clinical target response surfaces
Author(s) -
Lill Daniel,
Kümmel Anne,
Mitov Venelin,
Kaschek Daniel,
Gobeau Nathalie,
Schmidt Henning,
Timmer Jens
Publication year - 2022
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12779
Subject(s) - population , confidence interval , computer science , constant (computer programming) , pharmacodynamics , focus (optics) , statistics , mathematics , medicine , pharmacokinetics , pharmacology , physics , environmental health , optics , programming language
Abstract 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.