Pharmacokinetics and safety of a fully human hepatocyte growth factor antibody, AMG 102, in cynomolgus monkeys.
OBJECTIVE
AMG 102, a fully human monoclonal antibody that binds to hepatocyte growth factor (HGF), is a potential cancer therapeutic agent because of its ability to disrupt HGF/c-Met signaling pathways which have been implicated in most tumor types. To support a phase 1 study, the pharmacokinetic and safety profile of AMG 102 was assessed in cynomolgus monkeys.


METHODS
Serum concentration-time data from single- (i.v. and s.c.) and repeated-dose (i.v.) studies of up to 13 weeks were used for pharmacokinetic analysis. Safety was assessed in a single-dose safety pharmacology study with i.v. doses of 0 (vehicle), 25, 100, or 300 mg/kg and a 4-week toxicity study with once weekly i.v. doses of 0 (vehicle), 5, 25, or 100 mg/kg.


RESULTS
AMG 102 exhibited linear pharmacokinetics over a 600-fold dose range (0.5 to 300 mg/kg) with a mean terminal half-life of 5.6 days after i.v. dosing. Clearance and volume of distribution at steady state were 1.22 ml/h and 198.3 ml, respectively. Estimated bioavailability was 72% for s.c. administration. Antibody response to AMG 102 was observed in a small percentage of monkeys. No treatment-related cardiovascular, respiratory, or CNS changes were observed. Administration of AMG 102 for 4 weeks was well tolerated at doses up to 100 mg/kg. Potential treatment-related effects were limited to minimal/moderate gastric mucosa hemorrhage in the mid- and high-dose groups.


CONCLUSIONS
The nonclinical pharmacokinetic and safety profile of AMG 102 effectively supports clinical investigation.
Kakkar
Tarundeep
T
Department of Pharmacokinetics and Metabolism, Amgen Inc., Thousand Oaks, California 91320, USA. tkakkar@amgen.com
Ma
Mark
M
Zhuang
Yao
Y
Patton
Aaron
A
Hu
Zheng
Z
Mounho
Barbara
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006207:Half-Life; D017228:Hepatocyte Growth Factor / Q000276:immunology*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008657:Metabolic Clearance Rate; D012720:Severity of Illness Index; D013997:Time Factors; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C066855:HGF protein, human; C524459:rilotumumab; D017228:Hepatocyte Growth Factor