title: Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 approximately 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.
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA. roger.luo@bms.com
authors.forename: Feng R
authors.initials: FR
authors.lastname: Luo
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Amy
authors.initials: A
authors.lastname: Camuso
authors.forename: Richard
authors.initials: R
authors.lastname: Smykla
authors.forename: Kelly
authors.initials: K
authors.lastname: McGlinchey
authors.forename: Krista
authors.initials: K
authors.lastname: Fager
authors.forename: Christine
authors.initials: C
authors.lastname: Flefleh
authors.forename: Stephen
authors.initials: S
authors.lastname: Castaneda
authors.forename: Ivan
authors.initials: I
authors.lastname: Inigo
authors.forename: David
authors.initials: D
authors.lastname: Kan
authors.forename: Mei-Li
authors.initials: ML
authors.lastname: Wen
authors.forename: Robert
authors.initials: R
authors.lastname: Kramer
authors.forename: Anne
authors.initials: A
authors.lastname: Blackwood-Chirchir
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000037:antagonists & inhibitors*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000069439:Dasatinib; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D007275:Injections, Intravenous; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D011237:Predictive Value of Tests; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C082869:CRKL protein; D009687:Nuclear Proteins; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib