Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice.
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.
Denton
Cathrine L
CL
Animal Cancer Center, Veterinary Teaching Hospital, Colorado State University, ACC226, 300 W. Drake Rd., Fort Collins, CO 80523-1620, USA.
Gustafson
Daniel L
DL
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
C517975:AZD 6244; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine
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