Model Informed Approach to Support the Repurposing of Brompheniramine for Tumor Associated Neuroinflammation: Mechanistic Dose Prediction and Brain Exposure Assessment

Neuroinflammation is a hallmark of primary and metastatic brain tumors, contributing significantly to disease progression through proinflammatory cytokine regulation, blood brain barrier (BBB) disruption, and immune cell infiltration. The Histamine H1 Receptor (H1R) is expressed on glial, endothelial and tumor cells, and mediates proinflammatory signaling within the tumor microenvironment (TME). Inhibiting H1R may reduce neuroinflammation within the TME and promote anti-tumor environment, thereby limiting tumor progression. Brompheniramine, a first generation H1R antagonist, with proven BBB permeability is a promising repurposing candidate for targeting tumor associated neuroinflammation. However, the brain concentrations of brompheniramine and the duration of its exposure have not been reported, suggesting the need for additional evaluation to better understand its therapeutic potential. Thus, to predict brompheniramine’s brain concentrations and support dose selection for the treatment of neuroinflammation, we developed a physiologically based pharmacokinetic (PBPK) model using Simcyp®. Model input parameters were derived from a literature reported pharmacokinetic (PK) data. A surrogate pharmacodynamic (PD) EC50 of 90.42 ng/ml for anti-inflammatory efficacy was estimated using skin PD endpoints. Simulation trials were conducted for single and multiple dosing regimens, including the FDA approved adult dose of 24mg once daily (QD). Following a 2-week dosing regimen of 24mg QD, brain concentrations remained above the EC50for over 94% of the dosing interval. After reaching steady state at approximately 166.5h, concentrations remained above 2*EC50 for 78.5% of the interval, indicating sustained therapeutic exposure in brain tissue. The model indicated a good performance, with the predicted pharmacokinetics parameters falling within 0.5-2.0-fold range of observed clinical data. Overall, this study provides a mechanistic and quantitative framework for evaluating brompheniramine’s pharmacokinetics and provides guidance for dosing regimens in patients with glioblastoma or brain metastases. These findings highlight brompheniramine’s therapeutic potential to repurpose for tumor associated neuroinflammation.