Utilizing Minimal Physiologically Based Pharmacokinetic Modeling to Bridge Bevacizumab Pharmacokinetics from Adult to...

Bevacizumab is a humanized monoclonal antibody (mAb) approved to treat various cancers in adults and was investigated in pediatric patients. While the drug development of small molecules in pediatrics has greatly benefited from the use of physiologically-based pharmacokinetic (PBPK) modeling for pharmacokinetic (PK) extrapolation, such application remains relatively limited in mAbs. In this study, our objective was to evaluate the applicability of PBPK modeling in characterizing the age-dependent PK of bevacizumab. A minimal PBPK model was developed incorporating bevacizumab-specific drug parameters, with age-dependent physiological changes such as tissue volume, blood and lymphatic flow, and endogenous immunoglobulin G (IgG) levels, and validated using observed PK data in 786 adult and 141 pediatric patients from 23 bevacizumab clinical studies. The final model was applied to predict the exposure of bevacizumab in pediatric patients ranging from six months to 18 years old. Clinically observed bevacizumab PK data in adults following single or multiple dosing of 5, 10, and 15 mg/kg were generally within the 95% model prediction intervals. In pediatrics, the individually simulated bevacizumab concentrations were consistent with the individual observed data, including the pediatric patients as young as six months old. Sensitivity analysis revealed that endogenous IgG concentration and neonatal Fc receptors abundance play critical roles in bevacizumab PK in children. Overall, the PBPK model successfully bridges the bevacizumab PK from adult to pediatric patients by incorporating age-dependent physiological changes. This work represents a significant step forward in advancing the application of PBPK modeling of mAbs in children.