title: Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Male athymic, nude mice received subcutaneous inoculation of A375 human melanoma cells. Once tumors reached 400-700 mm(3), 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Animal Cancer Center, Veterinary Teaching Hospital, Colorado State University, ACC226, 300 W. Drake Rd., Fort Collins, CO 80523-1620, USA.
authors.forename: Cathrine L
authors.initials: CL
authors.lastname: Denton
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
mesh_terms: D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine
references.citation: Nature. 2006 Jan 19;439(7074):358-62
references.pmid: 16273091
references.citation: Clin Cancer Res. 2008 Jan 1;14(1):230-9
references.pmid: 18172275
references.citation: Drug Metab Dispos. 2003 May;31(5):510-8
references.pmid: 12695336
references.citation: J Clin Oncol. 2008 May 1;26(13):2139-46
references.pmid: 18390968
references.citation: Clin Cancer Res. 2003 Dec 15;9(17):6483-8
references.pmid: 14695152
references.citation: Melanoma Res. 2006 Dec;16(6):471-8
references.pmid: 17119447
references.citation: J Invest Dermatol. 2006 Jan;126(1):154-60
references.pmid: 16417231
references.citation: J Clin Oncol. 2005 Aug 10;23(23):5281-93
references.pmid: 16009947
references.citation: Mol Cancer Ther. 2007 Aug;6(8):2209-19
references.pmid: 17699718
references.citation: Br J Cancer. 2007 Feb 12;96(3):445-9
references.pmid: 17245336
references.citation: Melanoma Res. 2006 Aug;16(4):267-73
references.pmid: 16845322
references.citation: J Pharmacokinet Pharmacodyn. 2006 Jun;33(3):227-79
references.pmid: 16404503
references.citation: J Clin Oncol. 2004 Nov 15;22(22):4456-62
references.pmid: 15483017
references.citation: Methods Find Exp Clin Pharmacol. 2002;24 Suppl D:127-8
references.pmid: 12585231
references.citation: Clin Cancer Res. 2007 Mar 1;13(5):1576-83
references.pmid: 17332304
references.citation: Mol Cancer Ther. 2007 Jan;6(1):138-46
references.pmid: 17237274
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Cancer Res. 2002 Dec 1;62(23):6997-7000
references.pmid: 12460918
references.citation: J Clin Endocrinol Metab. 2007 Dec;92(12):4712-8
references.pmid: 17878251