Efficient simulation of clinical target response surfaces. (11th March 2022)

• Record Type: Journal Article
• Authors: Lill, Daniel; Kümmel, Anne; Mitov, Venelin; Kaschek, Daniel; Gobeau, Nathalie; Schmidt, Henning; Timmer, Jens
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 11:Number 4(2022)
• Page Start: 512
• Page End: 523
• Publication Date: 2022-03-11
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.12779
• Languages: English
• ISSNs: 2163-8306

Abstract

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.