title: Onartuzumab (MetMAb): using nonclinical pharmacokinetic and concentration-effect data to support clinical development.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Bender
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Reyes
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Nelson L 'shasha'
authors.initials: NL
authors.lastname: Jumbe
authors.forename: Mally
authors.initials: M
authors.lastname: Romero
authors.forename: Teresa
authors.initials: T
authors.lastname: Davancaze
authors.forename: Ihsan
authors.initials: I
authors.lastname: Nijem
authors.forename: Elaine
authors.initials: E
authors.lastname: Mai
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.forename: Amy
authors.initials: A
authors.lastname: Peterson
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Damico-Beyer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D009010:Monte Carlo Method; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011237:Predictive Value of Tests; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C584058:onartuzumab