Efficient simulation of clinical target response surfaces.

Autor: Lill D; IntiQuan GmbH, Basel, Switzerland.; Institute of Physics, University of Freiburg, Freiburg, Germany., Kümmel A; IntiQuan GmbH, Basel, Switzerland., Mitov V; IntiQuan GmbH, Basel, Switzerland., Kaschek D; IntiQuan GmbH, Basel, Switzerland., Gobeau N; Medicines for Malaria Venture, Geneva, Switzerland., Schmidt H; IntiQuan GmbH, Basel, Switzerland., Timmer J; Institute of Physics, University of Freiburg, Freiburg, Germany.; Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany.; Freiburg Center for Data Analysis and Modelling (FDM), University of Freiburg, Freiburg, Germany.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2022 Apr; Vol. 11 (4), pp. 512-523. Date of Electronic Publication: 2022 Mar 11.
DOI: 10.1002/psp4.12779
Abstrakt: 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.
(© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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