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Onartuzumab (MetMAb): using nonclinical pharmacokinetic and concentration-effect data to support clinical development

Hong Xiang1, Brendan C Bender, Arthur E Reyes

  • 1Authors' Affiliations: Departments of Pharmacokinetic and Pharmacodynamic Sciences, Translational Oncology, Bioanalytical Sciences, Biochemical and Cellular Pharmacology, and Portfolio Management and Operations, Genentech, Inc., South San Francisco; Quantitative Solutions, Menlo Park; Medivation, Inc., San Francisco; and Celgene, San Diego, California.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 30, 2013
PubMed
Abstract

Insights

Onartuzumab (MetMAb) exhibits faster clearance than typical antibodies. Dosing flexibility is supported, with 10-30 mg/kg every 3 weeks projected to achieve therapeutic onartuzumab concentrations.

Area of Science:

  • Pharmacokinetics and Pharmacodynamics
  • Monoclonal Antibody Therapeutics
  • Oncology Drug Development

Background:

  • Onartuzumab (MetMAb) is a bivalent monoclonal antibody targeting the MET receptor tyrosine kinase.
  • Understanding its pharmacokinetic (PK) profile is crucial for optimizing clinical dosing strategies.

Purpose of the Study:

  • To characterize onartuzumab pharmacokinetics in preclinical species.
  • To establish a concentration-effect relationship in tumor-bearing mice.
  • To project clinical PK parameters and determine target doses for onartuzumab therapy.

Main Methods:

  • Tumor growth inhibition models were used to determine tumoristatic concentrations (TSC) in mice.
  • Human PK parameters were extrapolated from cynomolgus monkey data using the species-invariant time method.
  • Monte Carlo simulations predicted patient exposure to target concentrations.

Main Results:

  • Onartuzumab demonstrated faster clearance (CL) in mice and monkeys compared to typical antibodies.
  • The estimated TSC in mice was 15 μg/mL.
  • Projected human CL ranged from 5.74 to 9.36 mL/d/kg, with a Q3W dose of 10-30 mg/kg predicted to achieve target trough concentrations (Ctrough ss) in ≥95% of patients.

Conclusions:

  • Onartuzumab's PK profile supports dose flexibility, allowing for Q1W to Q3W dosing regimens.
  • A target Ctrough ss of 15 μg/mL is proposed for clinical efficacy.
  • The projected human efficacious dose of 10-30 mg/kg Q3W is supported by PK/PD modeling.

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