title: Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.
abstract: OBJECTIVE
  Dasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit-risk profile of dasatinib 100 mg once daily, exposure-response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).
  
  
  METHODS
  Dasatinib exposure in patients with chronic myeloid leukemia in chronic phase was determined by population pharmacokinetic analysis of data from seven dasatinib clinical studies (N = 981), including the Phase III dose-optimization study (n = 567). Data from the Phase III study were then used to characterize exposure-response relationships for the four dasatinib treatment regimens investigated (100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily).
  
  
  RESULTS
  Major cytogenetic response was significantly (P < 0.01) associated with weighted average steady-state dasatinib plasma concentrations, and pleural effusion was significantly associated with trough concentration. Major cytogenetic response was also significantly associated with maintenance of uninterrupted dosing. The 100 mg once daily arm had the lowest steady-state trough concentration of the four dose arms investigated in the Phase III study, and although this arm also had the lowest weighted average steady-state dasatinib plasma concentration, it had the highest dose maintenance.
  
  
  CONCLUSIONS
  Dasatinib dose optimization to 100 mg once daily from 70 mg twice daily significantly minimizes adverse events while maintaining efficacy by exploiting differences in the measures of exposure associated with efficacy and safety.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, NJ, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Amit
authors.initials: A
authors.lastname: Roy
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Tai-Tsang
authors.initials: TT
authors.lastname: Chen
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
keywords: chronic myeloid leukemia; major cytogenetic response; pharmacokinetics; pleural effusion