This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Luo, F. R. Articles by Lee, F. Y. Search for Related Content PubMed PubMed Citation Articles by Luo, F. R. Articles by Lee, F. Y.

Dasatinib (BMS-354825) Pharmacokinetics and Pharmacodynamic Biomarkers in Animal Models Predict Optimal Clinical Exposure

Authors' Affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, New Jersey

Requests for reprints: Feng R. Luo, Oncology Drug Discovery, Bristol-Myers Squibb Company, K23-02, P.O. Box 4000, Princeton, NJ 08543. Phone: 609-252-3558; Fax: 609-252-6051; E-mail: roger.luo{at}bms.com.

Purpose: Chronic myeloid leukemia (CML) is caused by reciprocal translocation between chromosomes 9 and 22, forming BCR-ABL, a constitutively activated tyrosine kinase. Imatinib mesylate, a selective inhibitor of BCR-ABL, represents current frontline therapy for CML; however, emerging evidence suggests that drug resistance to imatinib may limit its long-term success. To improve treatment options, dasatinib (BMS-354825) was developed as a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. To date, dasatinib has shown promising anti-leukemic activity in preclinical models of CML and in phase I/II clinical studies in patients with imatinib-resistant or imatinib-intolerant disease.

Experimental Design: The pharmacokinetic and pharmacodynamic biomarkers of dasatinib were investigated in K562 human CML xenografts grown s.c. in severe combined immunodeficient mice. Tumoral levels of phospho-BCR-ABL/phospho-CrkL were determined by Western blot.

Results: Following a single oral administration of dasatinib at a preclinical efficacious dose of 1.25 or 2.5 mg/kg, tumoral phospho-BCR-ABL/phospho-CrkL were maximally inhibited at 3 hours and recovered to basal levels by 24 hours. The time course and extent of the inhibition correlated with the plasma levels of dasatinib in mice. Pharmacokinetic/biomarker modeling predicted that the plasma concentration of dasatinib required to inhibit 90% of phospho-BCR-ABL in vivo was 10.9 ng/mL in mice and 14.6 ng/mL in humans, which is within the range of concentrations achieved in CML patients who responded to dasatinib treatment in the clinic.

Conclusions: Phospho-BCR-ABL/phospho-CrkL are likely to be useful clinical biomarkers for the assessment of BCR-ABL kinase inhibition by dasatinib.

This article has been cited by other articles:

				M. G. Hollingshead Antitumor Efficacy Testing in Rodents J Natl Cancer Inst, November 5, 2008; 100(21): 1500 - 1510. [Abstract] [Full Text] [PDF]

				A. M. L. Coluccia, T. Cirulli, P. Neri, D. Mangieri, M. C. Colanardi, A. Gnoni, N. Di Renzo, F. Dammacco, P. Tassone, D. Ribatti, et al. Validation of PDGFR{beta} and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib Blood, August 15, 2008; 112(4): 1346 - 1356. [Abstract] [Full Text] [PDF]

				A. Veldurthy, M. Patz, S. Hagist, C. P. Pallasch, C.-M. Wendtner, M. Hallek, and G. Krause The kinase inhibitor dasatinib induces apoptosis in chronic lymphocytic leukemia cells in vitro with preference for a subgroup of patients with unmutated IgVH genes Blood, August 15, 2008; 112(4): 1443 - 1452. [Abstract] [Full Text] [PDF]

				A. Akhmetshina, C. Dees, M. Pileckyte, B. Maurer, R. Axmann, A. Jungel, J. Zwerina, S. Gay, G. Schett, O. Distler, et al. Dual inhibition of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis FASEB J, July 1, 2008; 22(7): 2214 - 2222. [Abstract] [Full Text] [PDF]

				S. D Baker Pharmacokinetic Considerations for Molecularly Targeted Therapy Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 705 - 709. [Abstract] [Full Text] [PDF]

				M. Kneidinger, U. Schmidt, U. Rix, K. V. Gleixner, A. Vales, C. Baumgartner, C. Lupinek, M. Weghofer, K. L. Bennett, H. Herrmann, et al. The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils Blood, March 15, 2008; 111(6): 3097 - 3107. [Abstract] [Full Text] [PDF]

				A. E. Schade, G. L. Schieven, R. Townsend, A. M. Jankowska, V. Susulic, R. Zhang, H. Szpurka, and J. P. Maciejewski Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation Blood, February 1, 2008; 111(3): 1366 - 1377. [Abstract] [Full Text] [PDF]