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

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogene sis and in pathological processes such as tumor growth, rheumatoid arthriti s, and ocular neovascularization. A recombinant humanized monoclonal antibo dy (rhuMAb), rhuMAb VEGF, has been developed to inhibit the effects of VEGF in the treatment of solid tumors. intravenous and s.c. pharmacokinetic stu dies were conducted in mice, rats, and cynomolgus monkeys. In addition, the tissue distribution of i.v. I-125-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 da ys in all species. After s.c. administration, rhuMAb VEGF had a bioavailabi lity of 69% in rats and 100% in mice and cynomolgus monkeys. Pharmacokineti c data in mice, rats, and cynomolgus monkeys were used to predict the pharm acokinetics of rhuMAb VEGF using allometric scaling in humans. The predicte d serum clearance of rhuMAb VEGF in humans was 2.4 ml/day/kg and the termin al half-life was 12 days. Two hours after i.v. bolus administration of I-12 5-rhuMAb VEGF in rabbits, trichloroacetic acid-precipitable radioactivity w as noted primarily in the plasma, with lesser amounts in highly perfused ti ssues such as kidneys, testes, spleen, heart, and lungs. At 48 h after dosi ng, trichloroacetic acid-precipitable radioactivity was noted in plasma wit h minimal distribution to testes, bladder, heart, lungs, and kidneys. Tissu e distribution and pharmacokinetic data indicate that rhuMAb VEGF is cleare d slowly and distributes to specific sites in the body.