Neural ODEs in Pharmacokinetics: Concepts and Applications

Machine Learning (ML) is a fast-evolving field, integrated in many of today’s scientific disciplines. With the recent development of Neural Ordinary Differential Equations (NODEs), ML provides a new tool to model dynamical systems in the field of pharmacology and pharmacometrics, such as pharmacokinetics (PK) or pharmacodynamics. The novel and conceptionally different approach of NODEs compared to classical PK modeling creates challenges but also provides opportunities for its application. In this manuscript, we introduce the functionality of NODEs and develop specific NODE structures based on PK principles. We discuss two challenges of NODEs, overfitting and extrapolation to unseen data, and we provide practical solutions to these problems. We illustrate concept and application of our proposed NODE approach with several PK modeling examples, including multi-compartmental, target-mediated drug disposition and delayed absorption behavior. In all investigated scenarios, the NODEs were able to describe well the data and simulate data for new subjects within the observed dosing range. Finally, we briefly demonstrate how NODEs can be combined with mechanistic models. This research work enhances understanding of how NODEs can be applied in PK analyses and illustrates the potential for NODEs in the field of pharmacology and pharmacometrics.