Latent Neural-ODE for Model-Informed Precision Dosing: Overcoming Structural Assumptions in Pharmacokinetics

TL;DR

This paper introduces a Latent Neural-ODE model for predicting tacrolimus AUC, offering a flexible, data-driven alternative to traditional pharmacokinetic models that better captures complex patient-specific dynamics.

Contribution

The study presents a novel Latent ODE approach that learns individualized pharmacokinetics directly from clinical data, overcoming rigid assumptions of existing models.

Findings

Latent ODE outperforms standard methods in simulation robustness.

Achieved higher precision in internal validation (RMSPE 7.99%).

Comparable external validation performance (RMSPE 10.82%).

Abstract

Accurate estimation of tacrolimus exposure, quantified by the area under the concentration-time curve (AUC), is essential for precision dosing after renal transplantation. Current practice relies on population pharmacokinetic (PopPK) models based on nonlinear mixed-effects (NLME) methods. However, these models depend on rigid, pre-specified assumptions and may struggle to capture complex, patient-specific dynamics, leading to model misspecification. In this study, we introduce a novel data-driven alternative based on Latent Ordinary Differential Equations (Latent ODEs) for tacrolimus AUC prediction. This deep learning approach learns individualized pharmacokinetic dynamics directly from sparse clinical data, enabling greater flexibility in modeling complex biological behavior. The model was evaluated through extensive simulations across multiple scenarios and benchmarked against two standard approaches: NLME-based estimation and the iterative two-stage Bayesian (it2B) method. We further performed a rigorous clinical validation using a development dataset (n = 178) and a completely independent external dataset (n = 75). In simulation, the Latent ODE model demonstrated superior robustness, maintaining high accuracy even when underlying biological mechanisms deviated from standard assumptions. Regarding experiments on clinical datasets, in internal validation, it achieved significantly higher precision with a mean RMSPE of 7.99% compared with 9.24% for it2B (p < 0.001). On the external cohort, it achieved an RMSPE of 10.82%, comparable to the two standard estimators (11.48% and 11.54%). These results establish the Latent ODE as a powerful and reliable tool for AUC prediction. Its flexible architecture provides a promising foundation for next-generation, multi-modal models in personalized medicine.