American Association for Cancer Research
10780432ccr130260-sup-figure_2.pdf (2.39 MB)

Supplementary Figure 2 from Onartuzumab (MetMAb): Using Nonclinical Pharmacokinetic and Concentration–Effect Data to Support Clinical Development

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journal contribution
posted on 2023-03-31, 17:41 authored by Hong Xiang, Brendan C. Bender, Arthur E. Reyes, Mark Merchant, Nelson L. ‘Shasha’ Jumbe, Mally Romero, Teresa Davancaze, Ihsan Nijem, Elaine Mai, Judy Young, Amy Peterson, Lisa A. Damico-Beyer

PDF file, 2444K, Basic goodness-of-fit plots for PK-PD modeling in KP4 tumor-bearing mice.



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. Clin Cancer Res; 19(18); 5068–78. ©2013 AACR.