Preclinical pharmacokinetics of MEHD7945A, a novel EGFR/HER3 dual-action antibody, and prediction of its human pharmacokinetics and efficacious clinical dose.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pharmacokinetics and Pharmacodynamics, Genentech, Inc, South San Francisco, CA 94080, USA. kamath.amrita@gene.com
Amrita V
AV
Kamath
Dan
D
Lu
Priyanka
P
Gupta
Denise
D
Jin
Hong
H
Xiang
Anne
A
Wong
Cecilia
C
Leddy
Lisa
L
Crocker
Gabriele
G
Schaefer
Mark X
MX
Sliwkowski
Lisa A
LA
Damico-Beyer
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D008252:Macaca fascicularis; D051379:Mice; D016513:Mice, SCID; D020893:Receptor, ErbB-3 / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007074:Immunoglobulin G; C569960:MEHD7945A; D066246:ErbB Receptors; D020893:Receptor, ErbB-3