Generation of realistic virtual adult populations using a model-based copula approach

Incorporating realistic sets of patient-associated covariates, i.e., virtual populations, in pharmacometric simulation workflows is essential to obtain realistic model predictions. Current covariate simulation strategies often omit or simplify dependency structures between covariates. Copula models...

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Bibliographic Details
Published inJournal of pharmacokinetics and pharmacodynamics Vol. 51; no. 6; pp. 735 - 746
Main Authors Guo, Yuchen, Guo, Tingjie, Knibbe, Catherijne A. J., Zwep, Laura B., van Hasselt, J. G. Coen
Format Journal Article
LanguageEnglish
Published New York Springer US 01.12.2024
Springer Nature B.V
Subjects
Age groups
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Body weight
Datasets
Ethnicity
Older people
Original Paper
Pharmacodynamics
Pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Random variables
Simulation
Trees
Veterinary Medicine/Veterinary Science
Copula
Covariate modeling
Virtual population
Pharmacometric simulation
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Summary:Incorporating realistic sets of patient-associated covariates, i.e., virtual populations, in pharmacometric simulation workflows is essential to obtain realistic model predictions. Current covariate simulation strategies often omit or simplify dependency structures between covariates. Copula models are multivariate distribution functions suitable to capture dependency structures between covariates with improved performance compared to standard approaches. We aimed to develop and evaluate a copula model for generation of adult virtual populations for 12 patient-associated covariates commonly used in pharmacometric simulations, using the publicly available NHANES database, including sex, race-ethnicity, body weight, albumin, and several biochemical variables related to organ function. A multivariate (vine) copula was constructed from bivariate relationships in a stepwise fashion. Covariate distributions were well captured for the overall and subgroup populations. Based on the developed copula model, a web application was developed. The developed copula model and associated web application can be used to generate realistic adult virtual populations, ultimately to support model-based clinical trial design or dose optimization strategies.
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ISSN:1567-567X
1573-8744
1573-8744
DOI:10.1007/s10928-024-09929-4