Toxicity and hemodynamic effects after single dose administration of MalPEG-hemoglobin (MP4) in rhesus monkeys.
Maleimide-polyethylene glycol-modified (MalPEG) hemoglobin, 4.3 g/dL (MP4; Hemospan), is a hemoglobin-based oxygen carrier consisting of human hemoglobin (Hb) modified with maleimide polyethylene glycol. This study evaluates the potential toxicity and hemodynamic actions of a single dose of MP4 administered by exchange transfusion to rhesus monkeys. Monkeys were administered MP4 (21 mL/kg, or approximately 30% of estimated blood volume) or an equivalent volume of lactated Ringer's solution (LR). In the toxicity study, blood samples were obtained predose and 3, 7, and 13 days after dosing for clinical chemistry and hematology. Animals were euthanized for complete necropsy and histopathology on day 3 or day 13. A separate group of animals was used for evaluation of arterial pressure, core temperature, and electrocardiogram, by telemetry, for 7 days after dosing with MP4. The results demonstrate no significant toxicity, with only modest, transient elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) on day 3. Mild anemia caused by hemodilution was observed at each time point in both groups, but to a slightly greater degree in the MP4-treated animals. Histologic observations included foamy or vacuolated macrophages in the spleen and marrow of the sternum, rib, and femur, representing the accumulation of test article or a metabolite. In the telemetry study, no changes occurred in arterial pressure, heart rate, or electrocardiogram attributable to administration of MP4 at any time for 7 days after administration. These results demonstrate that MP4 is safe and is without hemodynamic effects when administered as an exchange transfusion of 30% of estimated blood volume.
Young
Mark A
MA
Sangart, Inc., San Diego, CA 92121, USA. myoung@sangart.com
Malavalli
Ashok
A
Winslow
Nancy
N
Vandegriff
Kim D
KD
Winslow
Robert M
RM
D000410:Alanine Transaminase / Q000097:blood; D000740:Anemia / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D019963:Clinical Chemistry Tests; D004562:Electrocardiography; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects*; D006403:Hematologic Tests; D006454:Hemoglobins / Q000633:toxicity*; D006801:Humans; D007262:Infusions, Intravenous; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008253:Macaca mulatta; D008297:Male; D008301:Maleimides / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000633:toxicity*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests
D006454:Hemoglobins; D008301:Maleimides; C493836:maleimide-polyethylene glycol-modified hemoglobin, MP4; D011092:Polyethylene Glycols; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase