Comparison of subcutaneous and intravenous administration of the monoclonal antibody CSX-1004 on fentanyl-induced respiratory depression in squirrel monkeys

Background Fentanyl and related synthetic opioids remain major contributors to overdose mortality, primarily through opioid-induced respiratory depression. CSX-1004 is a fully human monoclonal antibody designed to bind fentanyl in the peripheral circulation and prevent its entry into the brain. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of intravenous (IV) and subcutaneous (SC) administration of CSX-1004 in squirrel monkeys and established a population PK (PopPK) model to support route extrapolation. Methods Protection against fentanyl-induced respiratory depression was assessed after administration of 40 mg/kg CSX-1004 using whole-body plethysmography over 28 days. Serum antibody concentrations were quantified by enzyme-linked immunosorbent assay, and PK parameters were characterized using noncompartmental and PopPK analyses. Results Both IV and SC administration produced substantial and durable attenuation of fentanyl-induced respiratory depression, resulting in a greater than 10-fold rightward shift in fentanyl potency that persisted for up to 28 days. SC CSX-1004 administration exhibited a maximum concentration of 491.7 ± 50.4 μg/mL at 48.0 ± 19.6 h (T max ) and an absolute bioavailability of 92.0% based on A U C 0 − ∞ . Terminal half-life was comparable between routes (∼272 h). A two-compartment PopPK model with first-order absorption and elimination adequately described the concentration–time data and demonstrated robust predictive performance. Serum concentrations and respiratory protection were lower after SC than after IV administration during the first 24–48 h, reflecting the absorption phase, and converged from Day 2 onward. Simulations indicated that SC and IV administration achieved overlapping systemic exposures beyond the absorption phase and equivalent concentrations associated with sustained respiratory protection through Day 28. Conclusion These findings demonstrate that SC administration of CSX-1004 provides PK and PD outcomes comparable to IV dosing, once absorption is complete, supporting SC delivery as a practical and clinically feasible approach for long-acting prophylaxis against fentanyl-induced respiratory depression.