Journal
REGULATORY TOXICOLOGY AND PHARMACOLOGY
Volume 69, Issue 3, Pages 512-523Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.yrtph.2014.05.019
Keywords
M2ES; Pre-clinical; Toxicokinetics; Safety; Rhesus monkeys
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Funding
- National Science & Technology Major Project [2009ZX09306-002]
- Major Scientific and Technological special project [2009ZX09102-243]
- Protgen Ltd. (Beijing, China)
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PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30 mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30 mg/kg body weight per day) for 3 months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. (C) 2014 The Authors. Published by Elsevier Inc.
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