Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys
- First Online:
- Cite this article as:
- Kakkar, T., Ma, M., Zhuang, Y. et al. Pharm Res (2007) 24: 1910. doi:10.1007/s11095-007-9316-2
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.
Materials and Methods
Serum concentration-time data from single-(IV and SC) and repeated-dose (IV) studies of up to 13 weeks were used for pharmacokinetic analysis. Safety was assessed in a single-dose safety pharmacology study with IV doses of 0 (vehicle), 25, 100, or 300 mg/kg and a 4-week toxicity study with once weekly IV doses of 0 (vehicle), 5, 25, or 100 mg/kg.
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 IV dosing. Clearance and volume of distribution at steady state were 1.22 ml/h and 198.3 ml, respectively. Estimated bioavailability was 72% for SC 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.
The nonclinical pharmacokinetic and safety profile of AMG 102 effectively supports clinical investigation.
Key wordsanti-HGF antibodycancerc-Methepatocyte growth factortyrosine kinase
Area under the concentration-time curve
Observed maximum concentration
Tyrosine kinase receptor for hepatocyte growth factor
Central nervous system
Enzyme-linked immunosorbent assay
First order conditional estimation
Immunoglobulin of subclass 2
Hepatocyte growth factor
First-order absorption rate
Recombinant human hepatocyte growth factor
Time of observed maximum concentration
Volume at steady-state
Volume of central compartment
Volume of peripheral compartment