MODELING DRUG-ORGAN INTERACTIONS AND OPTIMIZING IMMUNOTHERAPY: A QUANTITATIVE SYSTEMS PHARMACOLOGY AND ODRONEXTAMAB...

Cardiovascular and renal diseases remain major global health burdens, while B-cell non-Hodgkin lymphoma (B-NHL) continues to pose treatment challenges. Odronextamab, a bispecific antibody, offers therapeutic promise but is limited by dosing-related inflammatory responses. Quantitative Systems Pharmacology (QSP) modeling can provide mechanistic insights and guide dosing optimization.

To elucidate the mechanisms by which certain medications improve cardiovascular and renal function using computational models, and identify optimal dosing regimens for odronextamab in B-NHL patients to improve efficacy while minimizing inflammatory responses.

A QSP framework was developed using secondary data, integrating physiological, pharmacokinetic, and pharmacodynamic parameters. Simulations assessed the renal and cardiovascular impact of medications through variables such as urine composition, blood pressure, ejection fraction, and glomerular filtration rate. For odronextamab, mathematical models evaluated various dosing regimens based on interleukin-6 (IL-6) responses in three dosing groups. Model predictions were validated against real-world data and literature benchmarks.

Medications targeting cardiorenal function improved blood pressure (133.2±9.0 mmHg vs. 140±10.0 mmHg) and ejection fraction (50±3.2 vs. 65±3.6) in the experimental group. Computational modeling identified a novel mechanism of covert salt loss, alongside known sugar and water excretion effects, contributing to reduced tissue swelling and improved renal regulation. For odronextamab, Group C (variable dosing: 20 mg twice weekly) showed the most favorable IL-6 reduction (6.6±0.6 pg/ml), compared to Group A (7.5±0.8) and Group B (8.5±1.2). A refined split-dose schedule (0.7 mg in week 1, 4 mg in week 2, 20 mg in week 3) was proposed based on simulation outcomes.

This study provides mechanistic insights into how cardiorenal medications improve systemic function via sugar, water, and salt modulation. Additionally, it presents a validated, optimized dosing strategy for odronextamab that reduces IL-6 levels and enhances safety in B-NHL patients. Integrating QSP with real-world data supports personalized pharmacotherapy and underscores the utility of computational modeling in drug development and clinical decision-making.