Nathalie Paul ¹ Venetia Karamitsou ² Clemens Giegerich ² Afshin Sadeghi ¹ Moritz Lücke ¹ Britta Wagenhuber ² Alexander Kister ^1,3 Markus Rehberg ^2*

• ¹ Fraunhofer Institute for Intelligent Analysis and Information Systems, Sankt Augustin, North Rhine-Westphalia, Germany
• ² Sanofi (Germany), Frankfurt, Hesse, Germany
• ³ Federal Institute for Materials Research and Testing (BAM), Berlin, Berlin, Germany

In the context of in silico clinical trials, mechanistic computer models for pathophysiology and pharmacology (here quantitative systems pharmacology models, QSP) can greatly support the decision making for drug candidates and elucidate the (potential) response of patients to existing and novel treatments. These models are built on disease mechanisms and then parametrized using (clinical study) data. Clinical variability among patients is represented by alternative model parameterizations, called virtual patients. Despite the complexity of disease modeling itself, using individual patient data to build these virtual patients is particularly challenging given the highdimensional, potentially sparse and noisy clinical trial data.In this work, we investigate the applicability of simulation-based inference (SBI), an advanced probabilistic machine learning approach, for virtual patient generation from individual patient data and we develop and evaluate the concept of nearest patient fits (SBI NPF), which further enhances the fitting performance. At the example of rheumatoid arthritis (RA), where prediction of treatment response is notoriously difficult, our experiments demonstrate that the SBI approaches can capture large inter-patient variability in clinical data and can compete with standard fitting methods in the field. Moreover, since SBI learns a probability distribution over the virtual patient parametrization, it naturally provides the probabilitylikelihood for alternative parametrizations. The learned distributions allow us to generate highly probable alternative virtual patient populations for rheumatoid arthritis, which could potentially enhance greatly improves a robustthe assessment of drug candiatecandidates predictions if used forin in silico clinical trials.