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

Author

Amit C. Kolhe, University of Nebraska Medical CenterFollow

ORCID ID

0009-0002-1099-2296

Graduation Date

Summer 8-15-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Pharmaceutical Sciences

First Advisor

Daryl J. Murry

Second Advisor

Aaron M. Mohs

Third Advisor

Jered C. Garrison

Fourth Advisor

Tomas Helikar

Abstract

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.

Comments

2025 Copyright, the authors

Recommended Citation

Kolhe, Amit C., "Model Informed Approach to Support the Repurposing of Brompheniramine for Tumor Associated Neuroinflammation: Mechanistic Dose Prediction and Brain Exposure Assessment" (2025). Theses & Dissertations. 983.
https://digitalcommons.unmc.edu/etd/983