Pharmacokinetics and pharmacodynamics of dasatinib in the chronic phase of newly diagnosed chronic myeloid leukemia

• Published in: European journal of clinical pharmacology Vol. 72; no. 2; pp. 185 - 193
• Main Authors: Ishida, Yoji, Murai, Kazunori, Yamaguchi, Kohei, Miyagishima, Takuto, Shindo, Motohiro, Ogawa, Kazuei, Nagashima, Takahiro, Sato, Shinji, Watanabe, Reiko, Yamamoto, Satoshi, Hirose, Takayuki, Saitou, Souich, Yonezumi, Masakatsu, Kondo, Takeshi, Kato, Yuichi, Mochizuki, Noboru, Ohno, Keiko, Kishino, Satoshi, Kubo, Kohmei, Oyake, Tatsuo, Ito, Shigeki
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-02-2016; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antigens, CD34 - metabolism; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Chronic illnesses; Dasatinib - adverse effects; Dasatinib - pharmacokinetics; Dasatinib - pharmacology; Dasatinib - therapeutic use; Drug therapy; Female; Fusion Proteins, bcr-abl - antagonists & inhibitors; Fusion Proteins, bcr-abl - genetics; Humans; Kinetics; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Male; Middle Aged; Oncogene Protein v-crk - antagonists & inhibitors; Oncogene Protein v-crk - metabolism; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Phosphorylation - drug effects; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Treatment Outcome; Dasatinib; Pharmacodynamics; Half maximal inhibitory concentration; Molecular response; Phamacokinetics
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-015-1968-y

Purpose
Dasatinib is a novel, oral, multi-targeted kinase inhibitor of breakpoint cluster region-abelson (
BCR-ABL
) and Src family kinases. The study investigated pharmacokinetic (PK) and pharmacodynamic (PD) analyses of dasatinib in 51 newly diagnosed, chronic phase, chronic myeloid leukemia patients.
Methods
The dasatinib concentration required to inhibit 50 % of the CrkL (CT10 regulator of kinase like) phosphorylation in bone marrow CD34+ cells (half maximal (50 %) inhibitory concentration (IC50)
CD34+cells
) was calculated from each patient’s dose-response curve using flow cytometry. PK parameters were obtained from the population pharmacokinetic analysis of dasatinib concentrations in plasma on day 28 after administration.
Results
Early molecular responses were not significantly associated with PK or PD (IC50
CD34+cells
) parameters. However, the PK/PD parameter—time above IC50
CD34+cells
—significantly correlated with
BCR-ABL
transcript level at 3 months (correlation coefficient (CC) = −0.292,
P
 = 0.0375) and the reduction of
BCR-ABL
level at 1 or 3 months (CC = −0.404,
P
 = 0.00328 and CC = −0.356,
P
 = 0.0104, respectively). Patients with more than 12.6 h at time above IC50
CD34+cells
achieved a molecular response of 3.0 log reduction at 3 months and those more than 12.8 h achieved a deep molecular response less than 4.0 log reduction at 6 months at a significantly high rate (
P
 = 0.013, odds ratio = 4.8 and
P
 = 0.024, odds ratio = 4.3, respectively).
Conclusion
These results suggest that the anti-leukemic activity of dasatinib exhibits in a time-dependent manner and that exposure for more than 12.8 h at time above IC50
CD34+cells
could significantly improve prognosis.