Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose
| Autor: | Lisa A. Damico-Beyer, Mark X. Sliwkowski, Lisa Crocker, Denise Jin, Cecilia Leddy, Gabriele Schaefer, Amrita V. Kamath, Hong Xiang, Dan Lu, Anne Wong, Priyanka Gupta |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Receptor ErbB-3 medicine.drug_class Antineoplastic Agents Mice SCID Pharmacology Toxicology Monoclonal antibody Mice Pharmacokinetics Dual action Preclinical pharmacokinetics medicine Animals Humans Pharmacology (medical) biology Dose-Response Relationship Drug business.industry Antibodies Monoclonal ErbB Receptors Macaca fascicularis Oncology Immunoglobulin G biology.protein Female Antibody business Human cancer |
| Zdroj: | Cancer chemotherapy and pharmacology. 69(4) |
| ISSN: | 1432-0843 |
| Popis: | MEHD7945A is a novel dual-action monoclonal antibody in which each of the two antigen-binding fragments is capable of binding to EGFR and HER3 with high affinity. It is being evaluated as a potential therapy for human cancer. The purpose of these studies was to characterize the pharmacokinetics (PK) of MEHD7945A in mouse and monkey and predict its human PK and efficacious dose.PK of MEHD7945A was determined in SCID beige mice and cynomolgus monkeys after administration of single intravenous doses. Human PK profiles were projected from monkey PK profiles using a species-invariant time method, and human population PK parameters were estimated using a nonlinear, two-compartment model comprising specific (target-mediated) and nonspecific clearance pathways. The antitumor efficacy in mice bearing human tumor xenografts was used in conjunction with human PK projections to estimate human efficacious doses.The total clearance of MEHD7945A decreased with increase in dose in both mouse and monkey. The nonspecific clearance in monkey was estimated to be 14 mL/day/kg. The predicted nonspecific clearance range in humans was 6-10 mL/day/kg. Doses of 8-12 mg/kg administered every 2 weeks in humans were predicted to achieve exposure of 300 day μg/mL per week to match the efficacious exposure observed in xenograft models.The PK of MEHD7945A was nonlinear in mouse and monkey in the dose range tested. The nonspecific clearance in monkey was approximately twofold higher than typical humanized IgG1 antibodies. The projected human efficacious dose and dose regimen appear to be achievable in patients. |
| Databáze: | OpenAIRE |
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