Prior to clinical development, a comprehensive pharmacokinetic characterization of a novel drug is required to understand its exposure at the site of action and elimination. Accordingly, in vitro assays and animal pharmacokinetic studies are regularly employed to predict drug exposure in humans, which is often costly and time-consuming. For this reason, the prediction of human pharmacokinetics at the point of design would be of high value for drug discovery. Therefore, we have established a comprehensive data curation protocol that enables machine learning evaluation of 12 human in vivo pharmacokinetic parameters using only chemical structure information and available doses for 1001 unique compounds. These machine learning models were thoroughly investigated and validated using both an independent hold-out test set and AstraZeneca clinical data. In addition, the availability of preclinical predictions for a subset of internal clinical candidates allowed us to compare our in silico approach with state-of-the-art pharmacokinetic predictions. Based on this evaluation, three fit-for-purpose models for AUC PO (R_test² = 0.63; RMSE_test = 0.76), C_max PO (R_test² = 0.68; RMSE_test = 0.62), and Vd_ss IV (R_test² = 0.47; RMSE_test = 0.50) were identified. Based on the findings, our machine learning models have considerable potential for practical applications in drug discovery, such as influencing decision-making in drug discovery projects and progression of drug candidates toward the clinic.

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