Pharmaceutical Research

, Volume 24, Issue 10, pp 1910–1918

Pharmacokinetics and Safety of a Fully Human Hepatocyte Growth Factor Antibody, AMG 102, in Cynomolgus Monkeys

  • Tarundeep Kakkar
  • Mark Ma
  • Yao Zhuang
  • Aaron Patton
  • Zheng Hu
  • Barbara Mounho
Research Paper

DOI: 10.1007/s11095-007-9316-2

Cite this article as:
Kakkar, T., Ma, M., Zhuang, Y. et al. Pharm Res (2007) 24: 1910. doi:10.1007/s11095-007-9316-2

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.

Key words

anti-HGF antibodycancerc-Methepatocyte growth factortyrosine kinase

Abbreviations

AUC

Area under the concentration-time curve

CL

Systemic clearance

CL12

Intercompartmental clearance

Cmax,

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

Tmax

Time of observed maximum concentration

t1/2

Half-life

Vss

Volume at steady-state

V1

Volume of central compartment

V2

Volume of peripheral compartment

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Tarundeep Kakkar
    • 1
    • 4
  • Mark Ma
    • 1
  • Yao Zhuang
    • 2
  • Aaron Patton
    • 2
  • Zheng Hu
    • 2
  • Barbara Mounho
    • 3
  1. 1.Department of Pharmacokinetics and MetabolismAmgen Inc.Thousand OaksUSA
  2. 2.Clinical ImmunologyAmgen Inc.Thousand OaksUSA
  3. 3.Comparative Biology and Safety SciencesAmgen Inc.Thousand OaksUSA
  4. 4.Amgen Inc.Thousand OaksUSA