Safety and tolerability of amustaline/glutathione pathogen‐reduced red blood cells in neonatal rats

BACKGROUND: Amustaline (S-303)/glutathione (GSH) pathogen-reduced red blood cells (PR-RBCs) are in development for all adult and pediatric RBC transfusion indications, including neonates and infants. A neonatal rat model evaluated the safety and tolerability of PR-RBCs during growth and maturation. STUDY DESIGN AND METHODS: Repeated transfusions of 10 mL/kg syngeneic untreated (control) RBCs, PR-treated (study) or "high-degradant" PR-RBCs were transfused three-times weekly to neonatal Sprague-Dawley rats from post-natal day (PND) 4 through adolescence (PND 64). The high-degradant PR-RBCs utilized amustaline concentrations 5-fold higher than in the clinical process, without a terminal wash step. Toxicokinetic characteristics of the major amustaline degradant (S-300) were determined on PNDs 15, 29 and at study termination. Animal well-being, weight, sexual maturation, and cognitive development (using the Morris water maze) were monitored. On PND 65-68 terminal necropsy and pathological analyses were performed. RESULTS: All recipient groups demonstrated normal and comparable weight gain, sexual maturation, and cognitive development. There were no PR-RBC-related effects on clinical signs, clinical chemistry, gross- or histopathology, although all rats had polycythemia (Hb 16.6-17.0 g/dL) with reduced reticulocytes (0.6-1.4%) at study end. S-300 was cleared rapidly (<60 min in the study group) and did not accumulate in the blood. The high-degradant PR-RBC group, with 6.2-fold reduced species-specific scaling for increased basal metabolic rate, were exposed to ~11.8-fold higher S-300 exposure than expected in repeatedly-transfused patients, without apparent adverse effects. CONCLUSION: The neonatal rat study demonstrates the safety and tolerability of amustaline/GSH PR-RBCs for transfusion and supports clinical use in pediatric patients.