Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys
- Tarundeep KakkarAffiliated withDepartment of Pharmacokinetics and Metabolism, Amgen Inc.Amgen Inc. Email author
- , Mark MaAffiliated withDepartment of Pharmacokinetics and Metabolism, Amgen Inc.
- , Yao ZhuangAffiliated withClinical Immunology, Amgen Inc.
- , Aaron PattonAffiliated withClinical Immunology, Amgen Inc.
- , Zheng HuAffiliated withClinical Immunology, Amgen Inc.
- , Barbara MounhoAffiliated withComparative Biology and Safety Sciences, Amgen Inc.
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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 antibody cancer c-Met hepatocyte growth factor tyrosine kinase
- Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys
Volume 24, Issue 10 , pp 1910-1918
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- Springer US
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- anti-HGF antibody
- hepatocyte growth factor
- tyrosine kinase
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- Author Affiliations
- 1. Department of Pharmacokinetics and Metabolism, Amgen Inc., Thousand Oaks, California, 91320, USA
- 4. Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320, USA
- 2. Clinical Immunology, Amgen Inc., Thousand Oaks, California, 91320, USA
- 3. Comparative Biology and Safety Sciences, Amgen Inc., Thousand Oaks, California, 91320, USA