Virtual Patient Simulation Using Copula Modeling

Abstract

Virtual patient simulation is increasingly performed to support model‐based optimization of clinical trial designs or individualized dosing strategies. Quantitative pharmacological models typically incorporate individual‐level patient characteristics, or covariates, which enable the generation of virtual patient cohorts. The individual‐level patient characteristics, or covariates, used as input for such simulations should accurately reflect the values seen in real patient populations. Current methods often make unrealistic assumptions about the correlation between patient's covariates or require direct access to actual data sets with individual‐level patient data, which may often be limited by data sharing limitations. We propose and evaluate the use of copulas to address current shortcomings in simulation of patient‐associated covariates for virtual patient simulations for model‐based dose and trial optimization in clinical pharmacology. Copulas are multivariate distribution functions that can capture joint distributions, including the correlation, of covariate sets. We compare the performance of copulas to alternative simulation strategies, and we demonstrate their utility in several case studies. Our work demonstrates that copulas can reproduce realistic patient characteristics, both in terms of individual covariates and the dependence structure between different covariates, outperforming alternative methods, in particular when aiming to reproduce high‐dimensional covariate sets. In conclusion, copulas represent a versatile and generalizable approach for virtual patient simulation which preserve relationships between covariates, and offer an open science strategy to facilitate re‐use of patient data sets.

Pharmacodynamic modeling of colistin and imipenem againstin vitro Pseudomonas aeruginosabiofilms

“…As patient covariates (i.e. body weight and creatinine clearance) acted as significant factors in the prediction of the concentration profiles of imipenem, a virtual population generated from the NHANES copula (https://cocosim.lacdr.leidenuniv.nl/) was used as the input to obtain realistic covariates combinations and simulation results [24,25]. For colistin, we studied intravenous administration of 160 mg (2 MIU) every 8 hours of colistimethate sodium (CMS), the inactive prodrug of colistin, 720 mg (9 MIU) CMS every 24 h, and inhalation of 160 mg (2 MIU) CMS every 8 hours, consistent with recommended clinical dosing regimens [26].…”