NOTQ-05 MODEL-INFORMED RATIONALE FOR THE USE OF THE PLASMA KALLIKREIN INHIBITOR RZ402 AS A STEROID-SPARING STRATEGY IN PERITUMORAL BRAIN EDEMA FROM BRAIN METASTASES

Abstract

Peritumoral brain edema (PTBE) in patients with brain metastases is commonly managed with corticosteroids, particularly dexamethasone, which provides rapid symptomatic relief, but is associated with substantial toxicity during prolonged use. Clinical experience suggests that steroid tapering is frequently accompanied by edema recurrence, particularly in metastatic lesions. The plasma kallikrein–kinin system (KKS), a known regulator of vascular permeability and the validated therapeutic target in hereditary angioedema, represents an underexplored pathway contributing to PTBE. A series of linked computational models were developed to evaluate the potential contribution of plasma kallikrein activity to PTBE dynamics and to explore the theoretical impact of pharmacologic inhibition. Model components included: (1) a systems-level representation of the plasma kallikrein cascade and its relationship to blood–brain barrier permeability; (2) a tumor-class comparative framework calibrated to published dynamic contrast-enhanced MRI permeability parameters; (3) a Starling equation-based fluid flux model describing edema formation and clearance; and (4) a permeability decomposition framework incorporating VEGF and bradykinin associated contributions. Drug effects for the oral plasma kallikrein inhibitor RZ402 were incorporated using exposure-response assumptions derived from preclinical and clinical data. Sensitivity analyses were performed across a range of assumed bradykinin-mediated permeability fractions and edema clearance rates. Model simulations suggest that PTBE associated with brain metastases may exhibit clearance-limited behavior. Corticosteroid tapering achieved incomplete and transient reductions in edema volume with pronounced rebound dynamics in metastases compared to glioma. Incorporation of plasma kallikrein inhibition reduced the bradykinin-associated component of permeability, and was associated with sustained reductions in modeled edema during and after corticosteroid taper. This modeling framework supports the hypothesis that plasma kallikrein activity may contribute to PTBE dynamics and that pharmacologic inhibition could represent a potential strategy to maintain edema control during corticosteroid taper. The findings are hypothesis-generating and highlight a mechanistically distinct approach to steroid-sparing edema management in brain metastases.