Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. Export

@article{citeulike:3428747, abstract = {Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and in pathological processes such as tumor growth, rheumatoid arthritis, and ocular neovascularization. A recombinant humanized monoclonal antibody (rhuMAb), rhuMAb VEGF, has been developed to inhibit the effects of VEGF in the treatment of solid tumors. Intravenous and s.c. pharmacokinetic studies were conducted in mice, rats, and cynomolgus monkeys. In addition, the tissue distribution of i.v. 125I-rhuMAb VEGF was investigated in rabbits. At a dose of approximately 10 mg/kg, the clearance of rhuMAb VEGF from the serum was 15.7 ml/day/kg in mice, 4.83 ml/day/kg in rats, and 5.59 ml/day/kg in cynomolgus monkeys, and the terminal half-life ranged from 6 to 12 days in all species. After s.c. administration, rhuMAb VEGF had a bioavailability of 69\% in rats and 100\% in mice and cynomolgus monkeys. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of rhuMAb VEGF using allometric scaling in humans. The predicted serum clearance of rhuMAb VEGF in humans was 2.4 ml/day/kg and the terminal half-life was 12 days. Two hours after i.v. bolus administration of 125I-rhuMAb VEGF in rabbits, trichloroacetic acid-precipitable radioactivity was noted primarily in the plasma, with lesser amounts in highly perfused tissues such as kidneys, testes, spleen, heart, and lungs. At 48 h after dosing, trichloroacetic acid-precipitable radioactivity was noted in plasma with minimal distribution to testes, bladder, heart, lungs, and kidneys. Tissue distribution and pharmacokinetic data indicate that rhuMAb VEGF is cleared slowly and distributes to specific sites in the body.}, author = {Lin, Y. S. and Nguyen, C. and Mendoza, J. L. and Escandon, E. and Fei, D. and Meng, Y. G. and Modi, N. B.}, citeulike-article-id = {3428747}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/9862791}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=9862791}, citeulike-linkout-2 = {http://jpet.aspetjournals.org/cgi/content/full/288/1/371}, issn = {0022-3565}, journal = {The Journal of pharmacology and experimental therapeutics}, keywords = {allometric\_scaling, antibody, pharmacokinetics}, month = {January}, number = {1}, pages = {371--378}, posted-at = {2008-10-19 10:39:05}, priority = {2}, title = {Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/9862791}, volume = {288}, year = {1999} }

TY - JOUR ID - citeulike:3428747 L3 - citeulike-article-id:3428747 N2 - Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and in pathological processes such as tumor growth, rheumatoid arthritis, and ocular neovascularization. A recombinant humanized monoclonal antibody (rhuMAb), rhuMAb VEGF, has been developed to inhibit the effects of VEGF in the treatment of solid tumors. Intravenous and s.c. pharmacokinetic studies were conducted in mice, rats, and cynomolgus monkeys. In addition, the tissue distribution of i.v. 125I-rhuMAb VEGF was investigated in rabbits. At a dose of approximately 10 mg/kg, the clearance of rhuMAb VEGF from the serum was 15.7 ml/day/kg in mice, 4.83 ml/day/kg in rats, and 5.59 ml/day/kg in cynomolgus monkeys, and the terminal half-life ranged from 6 to 12 days in all species. After s.c. administration, rhuMAb VEGF had a bioavailability of 69% in rats and 100% in mice and cynomolgus monkeys. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of rhuMAb VEGF using allometric scaling in humans. The predicted serum clearance of rhuMAb VEGF in humans was 2.4 ml/day/kg and the terminal half-life was 12 days. Two hours after i.v. bolus administration of 125I-rhuMAb VEGF in rabbits, trichloroacetic acid-precipitable radioactivity was noted primarily in the plasma, with lesser amounts in highly perfused tissues such as kidneys, testes, spleen, heart, and lungs. At 48 h after dosing, trichloroacetic acid-precipitable radioactivity was noted in plasma with minimal distribution to testes, bladder, heart, lungs, and kidneys. Tissue distribution and pharmacokinetic data indicate that rhuMAb VEGF is cleared slowly and distributes to specific sites in the body. IS - 1 JF - The Journal of pharmacology and experimental therapeutics SN - 0022-3565 EP - 378 TI - Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. VL - 288 SP - 371 KW - allometric_scaling KW - antibody KW - pharmacokinetics AU - Lin, YS AU - Nguyen, C AU - Mendoza, JL AU - Escandon, E AU - Fei, D AU - Meng, YG AU - Modi, NB PY - 1999/01// UR - http://view.ncbi.nlm.nih.gov/pubmed/9862791 ER -