Physiologically based pharmacokinetic modeling for methotrexate in cerebrospinal fluid in humans

Methotrexate (MTX) is part of the treatment regimen for multiple cancers, including leukemia, which often metastasizes into the central nervous system (CNS). Intravenous MTX has limited distribution in the CNS requiring direct administration in the cerebrospinal fluid (CSF) to achieve therapeutic concentrations. However, there is limited data on dose-exposure relationships in pediatrics, particularly in children under 3 years old. The objective of this study was to develop a PBPK model for MTX to predict CSF concentrations following intraventricular administration in adults and children. Physiology-based sub-compartments of CSF were integrated into existing PBPK models of MTX disposition. Parameter optimization was based on literature data. The ability of the model to predict CSF concentrations following intraventricular administration through the Ommaya reservoir, particularly in young children, was evaluated based on data from St. Jude Children's Research Hospital. Sensitivity analysis was performed to identify critical parameters for predicting the time CSF MTX will be above 1 μM. Following Ommaya reservoir administration, 82.5%, 85.3%, and 84.3% of the observed CSF concentrations were within the 90% interval of predicted CSF concentrations for <5, >5, and 0.15-25-year-olds, respectively. The PBPK model was utilized to predict MTX concentration in CSF following the adaptive intraventricular dosing algorithms proposed in the previous study.