Efficient simulation of clinical target response surfaces.
Journal
CPT: pharmacometrics & systems pharmacology
ISSN: 2163-8306
Titre abrégé: CPT Pharmacometrics Syst Pharmacol
Pays: United States
ID NLM: 101580011
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
revised:
18
01
2022
received:
24
11
2021
accepted:
14
02
2022
pubmed:
25
2
2022
medline:
16
4
2022
entrez:
24
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35199969
doi: 10.1002/psp4.12779
pmc: PMC9007598
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
512-523Informations de copyright
© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.
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