Abstract: Objective In the experiment, recombinant human coagulation factor VIII is administered intravenously to Macaca fascicularis in a single and 30-day period to observe the potential toxicity and extent of the toxicity, and also the development and recovery of toxicity, so as to provide reference information for the clinical dose design and clinical adverse drug reactions monitoring. Methods The acute toxicity test was performed by lethal dose method. After single intravenous administration, the acute toxicity in Macaca fascicularis was observed. In the 30 days' repeated-dose toxicity experiment, 1 time/day administration was carried out for 30 days, and the recovery period was four weeks. Changes in various indexes of the Macaca fascicularis were observed. Results In the acute toxicity test, only the 61 250 IU·kg-1 group animals were observed lactate dehydrogenase (LDH) increased compared with self-controls before drug given. In the 30-day administration experiment, clinical symptoms associated with factor VIII antibodies and inhibitors, such as prolongation of APTT, hemorrhage, A/G reduction were found, and there were no toxic pathological changes clearly associated with administration. Also, no delayed or accumulation toxicity were observed. Conclusion The maximum tolerated dose of recombinant human factor VIII for single intravenous injection to Macaca fascicularis is greater than 61 250 IU·kg-1. No observed adverse effect level (NOAEL) of recombinant human factor VIII is 250 IU·kg-1 for the 30 days of repeated administration.

Key words: Macaca fascicularis, factor VIII, acute toxicity, repeated dose toxicity