David Ternant

Aims The exposure‐response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time‐dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure‐response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Methods Bevacizumab pharmacokinetics was described using target‐mediated drug disposition modelling. Relationships between target kinetics, progression‐free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic‐driven and response‐driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Results Estimated target‐mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels ( R 0 = 8.4 nM), steady‐state dissociation constant ( K SS = 10 nM) and antibody‐target complexes elimination constant ( k int = 0.52 day −1 ). The distribution of R 0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels ( R ) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. Conclusion This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in‐depth description of this relationship.

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim® and Mobi®). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim® was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi® was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (Cmax) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite.