PURPOSE: We characterized the pharmacokinetics of onartuzumab (MetMAb) in 
animals and determined a concentration-effect relationship in tumor-bearing mice 
to enable estimation of clinical pharmacokinetics and target doses.
EXPERIMENTAL DESIGN: A tumor growth inhibition model was used to estimate 
tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were 
projected from pharmacokinetics in cynomolgus monkeys by the species-invariant 
time method. Monte Carlo simulations predicted the percentage of patients 
achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 
3-week (Q3W) dosing.
RESULTS: Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 
mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 
3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft 
tumor-bearing mice was 15 μg/mL. Projected CL for humans in the linear dose 
range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. 
Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve 
Ctrough ss of 15 μg/mL in 95% or more of patients.
CONCLUSIONS: Onartuzumab pharmacokinetics differed from typical bivalent 
glycosylated monoclonal antibodies with approximately 2-times faster CL in the 
linear dose range. Despite this higher CL, xenograft efficacy data supported 
dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a 
TSC of 15 μg/mL as the Ctrough ss target. The projected human efficacious dose 
of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 μg/mL. These data show 
effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested 
in the clinic.