Pharmacokinetic (PK) and Pharmacodynamic (PD) Study Of Dasatinib In Chronic Phase Of Newly Diagnosed Chronic Myeloid Leukemia (CML-CP)

Ishida, Yoji; Murai, Kazunori; Yamaguchi, Kohei; Miyagishima, Takuo; Shindo, Motohiro; Ogawa, Kazuei; Nagashima, Takahiro; Sato, Shinji; Watanabe, Reiko; Yamamoto, Satoshi; Hirose, Takaaki; Kato, Yuichi; Yonezumi, Masakatsu; Kondo, Takeshi; Mochizuki, Nobuo; Ohno, Keiko; Kishino, Satoshi; Ito, Shigeki; Kubo, Komei; Saito, Sohichi

doi:10.1182/blood.V122.21.4031.4031

Abstract

Purpose

Dasatinib is a novel kinase inhibitor of BCR-ABL and SRC family kinases. Dasatinib has shown promising anti-leukemic activity in chronic myeloid leukemi (CML). Tounderstand how to administer dasatinib with best efficacy and less adverse events, the pharmacokinetic (PK) properties of dasatinib and the relationship of PK and pharmacodynamic (PD) characteristics were investigated in newly diagnosed CML-chronic phase (CP) patients.

Methods and Materials

The PK analysis of dasatinib: The plasma concentrations of dasatinib (1, 2, 4 hr after taking dasatinib post 28 days) were determined by Francia's method using high performance liquid chromatography with mass spectrometry. PK analysis was performed using Phoenix^â NLME^â1.2. The maximum plasma concentration (Cmax) was determined by visually inspecting the profiles of plasma drug levels.

PD analysis of dasatinib: Phospho-CrkL in CD 34 positive cells was analyzed by flow cytometry using anti-phospho-CrkL (Tyr207) antibody after incubation of bone marrow mononuclear cells in the presence of dasatinib for 2 hours.

PK/PD analysis: Area under the curve (AUC) and time above IC50 were calculated using Phonix WinNonlin 6.3.

Results

Twenty-eight newly diagnosed CML-CP patients were included. The correlation between the efficacy and PK/PD parameters were analyzed using Peason's correlation coefficient test (Table1). The efficacy(expression of bcr/abl at 1 month) was not correlated with AUC, Cmax, AUC/IC50 and Cmax/IC50 but significantly correlated with TAIC50 (r=0.4763, p=0.0104). The reduction rate at 1 month was correlated significantly with only TAIC50(r=0.5136, p=0.0052)(Figure 2). Eight cases reached MMR at 3 month among 15, whose TAIC50s were more than 12 hrs(53.3%), while only 2 cases reached MMR among 13, whose those were less than 12 hrs(15.4%).