Yuchen Guo, Tingjie Guo, Catherijne A J Knibbe, Laura B Zwep, J G Coen van Hasselt
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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 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.
期刊介绍:
Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.