ETODA: Automatic three-dimensional error tolerance grid generation for dosage adaptation in precision medicine

Model-informed precision dosing (MIPD) relies on drug concentration measurements to individualize dosage regimens, yet emerging point-of-care (POC) technologies may introduce substantial measurement uncertainty compared with conventional laboratory assays. Existing frameworks lack systematic tools to evaluate how such inaccuracies propagate to dosage adaptation decisions and affect therapeutic outcomes across different sampling times. We propose ETODA (error tolerance of dosage adaptation), a computational framework that constructs automatic three-dimensional error-tolerance grids to quantify the robustness of dosage decisions under measurement uncertainty.

By integrating population pharmacokinetic (popPK) models, patient-specific covariates, Bayesian posterior estimation, and Monte Carlo simulations, ETODA maps the relationship between measured and true drug concentrations, sampling time, and resulting therapeutic risk. The framework was applied to imatinib and vancomycin as model drugs with distinct therapeutic targets and dosing strategies, using 50 × 50 grids from simulated steady-state concentration ranges.

The grids revealed drug-specific responses to discrepancies between measured and true concentrations, and highlighted the influence of sampling time on therapeutic classification. For imatinib, peak sampling at 4 h yielded the highest distribution-weighted therapeutic-target classification percentage (52.24%), while the distribution-weighted percentage of grid points in the inefficacy alarm range increased to 53.47% at 24 h. For vancomycin, AUC/MIC-based monitoring showed higher distribution-weighted therapeutic-target classification percentages and lower distribution-weighted alarm-level classification percentages than trough-based monitoring across the evaluated sampling times.

ETODA provides a robustness-evaluation layer that operates on top of existing popPK and MIPD workflows, mapping measurement error onto downstream dose decisions and therapeutic-risk classifications. It thereby supports more robust MIPD and informs the design of POC monitoring technologies for safer, more effective precision dosing.