title: Pharmacokinetics of dasatinib for Philadelphia-positive acute lymphocytic leukemia with acquired T315I mutation.
abstract: BACKGROUND
  The BCR-ABL T315I kinase domain mutation is insensitive to dasatinib therapy for Philadelphia-positive acute lymphoid leukemia (Ph + ALL) patients. Resistant T315I clone may be present prior to initiating dasatinib, which could expand under selective pressures during treatment. However, it is also possible that Ph + ALL patients newly acquire the T315I mutation during dasatinib therapy. Despite the potent inhibition of BCR-ABL kinase by dasatinib, little is known about the relationship between dasatinib pharmacokinetics and the emergence of kinase domain mutations in vivo.
  
  
  METHODS
  To determine whether plasma dasatinib pharmacokinetics influences the emergence of BCR-ABL mutations, we measured plasma dasatinib levels in 11 Ph + ALL patients undergoing dasatinib monotherapy.
  
  
  RESULTS
  Bone marrow relapse occurred in 5 of the 11 Ph + ALL patients (45%). Importantly, a T315I mutation was detected in 4 of the 5 relapsed patients, despite the absence of BCR-ABL mutations in any patient at baseline. The median plasma concentration at 2 hours (C(2h)), the median plasma maximum concentration (C(max)), and the median area under the observed plasma concentration-time curve from 0 to 4 hours (AUC(0-4)) were all significantly lower in patients with T315I than those without the mutation (C(2h), 22.3 ng/mL vs. 111.6 ng/mL, P = 0.0242; C(max), 43.8 ng/mL vs. 112.4 ng/mL, P = 0.0242; AUC(0-4), 108.3 ng·h/mL vs. 268.3 ng·h/mL, P = 0.0061, respectively).
  
  
  CONCLUSIONS
  These data indicate that the emergence of the T315I mutation among Ph + ALL patients treated with dasatinib is, in part, dependent on plasma dasatinib pharmacokinetics. Notably, these data also suggest that newly acquired BCR-ABL mutations may be inhibited by an increased exposure of dasatinib.
authors.affiliation: Dept. of Hematology Nephrology and Rheumatology, Akita Univ. Graduate School of Medicine, Akita, Japan. naotot@doc.med.akita-u.ac.jp
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sawada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib