Abstract
Purpose
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.
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 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.
Conclusions
The nonclinical pharmacokinetic and safety profile of AMG 102 effectively supports clinical investigation.
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Abbreviations
- AUC:
-
Area under the concentration-time curve
- CL:
-
Systemic clearance
- CL12:
-
Intercompartmental clearance
- C max, :
-
Observed maximum concentration
- cMet:
-
Tyrosine kinase receptor for hepatocyte growth factor
- CNS:
-
Central nervous system
- ECG:
-
Electrocardiogram
- ELISA:
-
Enzyme-linked immunosorbent assay
- F:
-
Apparent bioavailability
- FOCE:
-
First order conditional estimation
- IgG2 :
-
Immunoglobulin of subclass 2
- IV:
-
Intravenous
- HGF:
-
Hepatocyte growth factor
- Ka:
-
First-order absorption rate
- OD:
-
Optical density
- PK:
-
Pharmacokinetics
- rhHGF:
-
Recombinant human hepatocyte growth factor
- SC:
-
Subcutaneous
- T max :
-
Time of observed maximum concentration
- t 1/2 :
-
Half-life
- V ss :
-
Volume at steady-state
- V1:
-
Volume of central compartment
- V2:
-
Volume of peripheral compartment
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Acknowledgements
The authors would like to thank Dr. Parnian Zia-Amirhosseini for reviewing this manuscript and providing helpful comments and Dr. Laura Healy for performing a peer review of the microscopic findings in the 4-week toxicity study. Ms. Tsui-Chern Cheah contributed to the technical preparation of this manuscript.
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Kakkar, T., Ma, M., Zhuang, Y. et al. Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys. Pharm Res 24, 1910–1918 (2007). https://doi.org/10.1007/s11095-007-9316-2
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DOI: https://doi.org/10.1007/s11095-007-9316-2