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Toxicol Sci 2012 Jun;127(2):567-81

Down selection of polymerized bovine hemoglobins for use as oxygen releasing therapeutics in a guinea pig model.

Baek JH, Zhou Y, Harris DR, Dominik SJ, Palmer AF, Buehler PW


Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as resuscitative fluids for use in multiple medical applications and in lieu of blood transfusion. However, cardiovascular, central nervous system and renal adverse events have largely impeded progress. This has prompted a need to evaluate novel down selection approaches for HBOCs prior to in depth pre-clinical and clinical safety testing. In the present study, polymerized bovine Hbs (PolybHbs) were prepared with increasing ratios of glutaraldehyde to bovine Hb (10:1, 20:1, 30:1, 40:1). The optimal PolybHb candidate selection was based on a priori determined in vivo response to include a long circulating PolybHb with no measurable renal exposure, minimal cardiovascular response, limited oxidation to met-Hb in vitro or in circulation and absence of acute end organ toxicity. Guinea pigs were dosed via a 50% blood for PolybHb exchange transfusion. Data suggested that the 30:1 preparation exhibited maximum circulatory exposure (AUC(0-¿)) with the lowest level of oxidation (plasma met-Hb formation) and minimal (<10%) blood pressure elevation. Additionally, the 30:1 preparation was absent renal iron deposition as well as abnormal glomerular/tubular histopathology or serum creatinine elevation. Clearance pathways predominantly followed those consistent with endogenous Hb clearance based pathways. Therefore, data confirmed the ability to select a single PolybHb from a small library of HBOCs based on a priori determined characteristics. Moreover, the approach to down selection described could be applied to enhance the early predictability of human safety for this class of biological therapeutics to optimize for specific indications.

Category: Journal Article
PubMed ID: #22416071 DOI: 10.1093/toxsci/kfs109
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-12-17 Entry Last Modified: 2012-08-29