Actionable Predictions of Human Pharmacokinetics at the Drug Design Stage

• Published in: Molecular pharmaceutics Vol. 21; no. 9; pp. 4356 - 4371
• Main Authors: Komissarov, Leonid, Manevski, Nenad, Groebke Zbinden, Katrin, Schindler, Torsten, Zitnik, Marinka, Sach-Peltason, Lisa
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.09.2024
• Subjects: Drug Design; Humans; Machine Learning; Pharmaceutical Preparations - chemistry; Pharmacokinetics; transfer learning; clinical; uncertainty quantification; pharmacokinetics; graph neural networks; PK; machine learning; human; dataset; predictions
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.4c00311

We present a novel computational approach for predicting human pharmacokinetics (PK) that addresses the challenges of early stage drug design. Our study introduces and describes a large-scale data set of 11 clinical PK end points, encompassing over 2700 unique chemical structures to train machine learning models. To that end multiple advanced training strategies are compared, including the integration of in vitro data and a novel self-supervised pretraining task. In addition to the predictions, our final model provides meaningful epistemic uncertainties for every data point. This allows us to successfully identify regions of exceptional predictive performance, with an absolute average fold error (AAFE/geometric mean fold error) of less than 2.5 across multiple end points. Together, these advancements represent a significant leap toward actionable PK predictions, which can be utilized early on in the drug design process to expedite development and reduce reliance on nonclinical studies.