Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms

Publication: J Pharmacokinet Pharmacodyn
Software: GastroPlus®


Physiologically based pharmacokinetic (PBPK) models can be used to leverage physiological and in vitro data to predict monoclonal antibody (mAb) concentrations in serum and tissues. However, it is currently not known how consistent predictions of mAb disposition are across PBPK modelling platforms. In this work PBPK simulations of IgG, adalimumab and infliximab were compared between three platforms (Simcyp, PK-Sim, and GastroPlus). Accuracy of predicted serum and tissue concentrations was assessed using observed data collected from the literature. Physiological and mAb related input parameters were also compared and sensitivity analyses were carried out to evaluate model behavior when input values were altered. Differences in serum kinetics of IgG between platforms were minimal for a dose of 1 mg/kg, but became more noticeable at higher dosages (> 100 mg/kg) and when reference (healthy) physiological input values were altered. Predicted serum concentrations of both adalimumab and infliximab were comparable across platforms, but were noticeably higher than observed values. Tissue concentrations differed remarkably between the platforms, both for total- and interstitial fluid (ISF) concentrations. The accuracy of total tissue concentrations was within a three-fold of observed values for all tissues, except for brain tissue concentrations, which were overpredicted. Predictions of tissue ISF concentrations were less accurate and were best captured by GastroPlus. Overall, these simulations show that the different PBPK platforms generally predict similar mAb serum concentrations, but variable tissue concentrations. Caution is therefore warranted when PBPK models are used to simulate effect site tissue concentrations of mAbs without data to verify the predictions.

By Pieter-Jan De Sutter, Elke Gasthuys & An Vermeulen