Comparing the applications of machine learning, PBPK, and population pharmacokinetic models in pharmacokinetic drug–drug interaction prediction

The gold‐standard approach for modeling pharmacokinetic mediated drug–drug interactions is the use of physiologically‐based pharmacokinetic modeling and population pharmacokinetics. However, these models require extensive amounts of drug‐specific data generated from a wide variety of in vitro and in vivo models, which are later refined with clinical data and system‐specific parameters. Machine learning has the potential to be utilized for the prediction of drug–drug interactions much earlier in the drug discovery cycle, using inputs derived from, among others, chemical structure. This could lead to refined chemical designs in early drug discovery. Machine‐learning models have many advantages, such as the capacity to automate learning (increasing the speed and scalability of predictions), improved generalizability by learning from multicase historical data, and highlighting statistical and potentially clinically significant relationships between input variables. In contrast, the routinely used mechanistic models (physiologically‐based pharmacokinetic models and population pharmacokinetics) are currently considered more interpretable, reliable, and require a smaller sample size of data, although insights differ on a case‐by‐case basis. Therefore, they may be appropriate for later stages of drug–drug interaction assessment when more in vivo and clinical data are available. A combined approach of using mechanistic models to highlight features that can be used for training machine‐learning models may also be exploitable in the future to improve the performance of machine learning. In this review, we provide concepts, strategic considerations, and compare machine learning to mechanistic modeling for drug–drug interaction risk assessment across the stages of drug discovery and development.