CPT: Pharmacometrics & Systems Pharmacology (Apr 2022)

Efficient simulation of clinical target response surfaces

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

DOI
https://doi.org/10.1002/psp4.12779
Journal volume & issue
Vol. 11, no. 4
pp. 512 – 523

Abstract

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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.