Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure–response analysis of a Phase III study

Xiaoning Wang,¹ Amit Roy,² Andreas Hochhaus,³ Hagop M Kantarjian,⁴ Tai-Tsang Chen,⁵ Neil P Shah<sup>6

1</sup>Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, NJ, USA; ²Clinical Pharmacology and Pharmacometrics, Research and Development, Bristol-Myers Squibb, Lawrenceville, NJ, USA; ³Hematology/Oncology, Jena University Hospital, Jena, Germany; ⁴Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; ⁵Department of Global Biometric Sciences, Bristol-Myers Squibb, Wallingford, CT, USA; ⁶Hematology/Oncology, University of California, San Francisco School of Medicine, San Francisco, CA, USA

Purpose: 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).
Patients and 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.
Conclusion: 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.

Keywords: chronic myeloid leukemia, pharmacokinetics, major cytogenetic response, pleural effusion