A Fourteen-Day Observation and Pharmacokinetic Evaluation after a Massive Intravenous Infusion of Hemoglobin-Vesicles (Artificial Oxygen Carriers) in Cynomolgus Monkeys

Abstract

Hemoglobin-vesicles (HbV) are a cellular type hemoglobin-based oxygen carrier in which a concentrated hemoglobin solution is encapsulated within a phospholipid vesicle (liposome). Although it was previously revealed that HbV possesses a higher biocompatibility, low toxicity and no accumulation in the body in an animal model, these assessments were limited to the use of rodents, including mice, rats and rabbits as models. The aim of this study was to observe the effects of the administration of HbV in a nonhuman primate. For this purpose, cynomolgus monkeys were used as the model and the systematic response, serum biochemical analysis and pharmacokinetic properties were monitored for 14 days after a massive intravenous injection of HbV at a putative dose (1400 mg Hb/ kg, 17.5 mL/kg). All of the monkeys tolerated the massive amount of injected HbV and survived, and no abnormal behavior was observed. The systematic response and serum biochemical analysis were overall normal, except for a transient elevation in alanine aminotransferase levels. In addition, the levels of phospholipids, total cholesterol and total bilirubin, metabolites of hemoglobin and lipid components of HbV, were increased after HbV administration. In the pharmacokinetic study, HbV was retained for a sufficient period to permit it to function as an alternative to red blood cells and showed good metabolic properties without accumulation in the bloodstream. In conclusion, this is the first report of biological reactions and a pharmacokinetic evaluation for a 14 day period after a massive intravenous injection of HbV in a primate. The results obtained in this study provide useful information, not only for the development of further optimized HbV but also for designing relevant and rational protocols for clinical trials.