Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice | springermedicine.com

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Cancer Chemotherapy and Pharmacology

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01-02-2011 | Original Article

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

Authors: Cathrine L. Denton, Daniel L. Gustafson

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2011

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Abstract

Purpose

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 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.

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.

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1.

Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D, Molina JR, Hanson LJ, Gore L, Chow L, Leong S, Maloney L, Gordon G, Simmons H, Marlow A, Litwiler K, Brown S, Poch G, Kane K, Haney J, Eckhardt SG (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26:2139–2146CrossRefPubMed

2.

Ball DW, Jin N, Rosen DM, Dackiw A, Sidransky D, Xing M, Nelkin BD (2007) Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. J Clin Endocrinol Metab 92:4712–4718CrossRefPubMed

3.

Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, Einhorn E, Herlyn M, Minna J, Nicholson A, Roth JA, Albelda SM, Davies H, Cox C, Brignell G, Stephens P, Futreal PA, Wooster R, Stratton MR, Weber BL (2002) BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 62:6997–7000PubMed

4.

Csajka C, Verotta D (2006) Pharmacokinetic-pharmacodynamic modelling: history and perspectives. J Pharmacokinet Pharmacodyn 33:227–279CrossRefPubMed

5.

Danhof M, Visser SA (2002) Pharmaco-electroencephalography and pharmacokinetic-pharmacodynamic modeling in drug development: focus on preclinical steps. Methods Find Exp Clin Pharmacol 24(Suppl D):127–128PubMed

6.

Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD (2007) AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther 6:2209–2219CrossRefPubMed

7.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954CrossRefPubMed

8..

Dummer R, Robert C, Chapman PB, Sosman JA, Middleton M, Bastholt L, Kemsley K, Cantarini MV, Morris C, Kirkwood JM (2008) AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: an open-label, randomized, multicenter, phase II study. J Clin Oncol 26:15S

9.

Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J (2006) NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16:471–478CrossRefPubMed

10.

Goel VK, Lazar AJ, Warneke CL, Redston MS, Haluska FG (2006) Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126:154–160CrossRefPubMed

11.

Haass NK, Sproesser K, Nguyen TK, Contractor R, Medina CA, Nathanson KL, Herlyn M, Smalley KS (2008) The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel. Clin Cancer Res 14:10CrossRef

12.

Huynh H, Soo KC, Chow PK, Tran E (2007) Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther 6:138–146CrossRefPubMed

13.

Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY, Hanson L, DeLuca P, Bruzek L, Piens J, Asbury P, Van Becelaere K, Herrera R, Sebolt-Leopold J, Meyer MB (2005) Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol 23:5281–5293CrossRefPubMed

14.

Mager DE, Wyska E, Jusko WJ (2003) Diversity of mechanism-based pharmacodynamic models. Drug Metab Dispos 31:510–518CrossRefPubMed

15.

Omholt K, Platz A, Kanter L, Ringborg U, Hansson J (2003) NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res 9:6483–6488PubMed

16.

Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, Redman B, Thomas NE, Gruber SB (2006) BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res 16:267–273CrossRefPubMed

17.

Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB, Hamid O, Varterasian M, Asbury P, Kaldjian EP, Gulyas S, Mitchell DY, Herrera R, Sebolt-Leopold JS, Meyer MB (2004) Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol 22:4456–4462CrossRefPubMed

18.

Smalley KS, Contractor R, Haass NK, Lee JT, Nathanson KL, Medina CA, Flaherty KT, Herlyn M (2007) Ki67 expression levels are a better marker of reduced melanoma growth following MEK inhibitor treatment than phospho-ERK levels. Br J Cancer 96:445–449CrossRefPubMed

19.

Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362CrossRefPubMed

20.

Teicher BA (2002) Tumor models in cancer research. Humana Press, Totowa

21.

Yeh TC, Marsh V, Bernat BA, Ballard J, Colwell H, Evans RJ, Parry J, Smith D, Brandhuber BJ, Gross S, Marlow A, Hurley B, Lyssikatos J, Lee PA, Winkler JD, Koch K, Wallace E (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13:1576–1583CrossRefPubMed

Title: Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice
Authors: Cathrine L. Denton
Daniel L. Gustafson
Publication date: 01-02-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1323-z

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