Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 349–360

Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice

Original Article

DOI: 10.1007/s00280-010-1323-z

Cite this article as:
Denton, C.L. & Gustafson, D.L. Cancer Chemother Pharmacol (2011) 67: 349. doi:10.1007/s00280-010-1323-z



AZD6244 (ARRY-142886) (AstraZeneca, Macclesfield, UK) is a novel small molecule MEK1/2 inhibitor that is currently being tested in Phase II trials. With the recent publication of human pharmacokinetic data from clinical studies, we now know the achievable levels and range of AZD6244 exposure in humans. This study aimed to describe the pharmacokinetic profile of AZD6244 in mice in order to design preclinical studies that recapitulate exposure levels in humans.


Male athymic, nude mice received subcutaneous inoculation of A375 human melanoma cells. Once tumors reached 400–700 mm3, mice were given a single dose of either 5 or 10 mg/kg AZD6244 via oral gavage. Additionally, a subset of mice was dosed once daily for 1 week (10 mg/kg). Mice were killed and plasma and tissues were collected at various time points after the last dose. Samples were analyzed by LC/MS/MS for AZD6244 concentration. Additionally, pharmacodynamic endpoints such as tumor proliferation and ERK phosphorylation were analyzed at various time points after the last dose.


After either a single dose or at steady state, at clinically equivalent exposures, AZD6244 effectively inhibits ERK phosphorylation and suppresses proliferation. Furthermore, we describe a hysteretic relationship between the pharmacokinetics and the pharmacodynamics of AZD6244 and both target and pharmacologic responses.


The information presented herein will drive the rational design of pre-clinical studies that are not only relevant to the clinical setting, but also pave the way to understand the biological response to AZD6244 treatment.


AZD6244 MEK inhibitor PK/PD relationship Hysteresis 



Mitogen activated protein kinase







Supplementary material

280_2010_1323_MOESM1_ESM.tif (432 kb)
Supplementary material 1 (TIFF 431 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Animal Cancer Center, Veterinary Teaching HospitalColorado State UniversityFort CollinsUSA
  2. 2.University of Colorado Cancer CenterAuroraUSA
  3. 3.Department of Clinical Sciences, Veterinary Teaching HospitalColorado State UniversityFort CollinsUSA

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