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


CONCLUSIONS
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.
Iwate Medical University School of Medicine, Morioka, Japan. yishida@iwate-med.ac.jp.|Department of Hematology and Oncology, Internal Medicine, Iwate Medical University School of Medicine, 19-1, Uchimaru, Morioka, Iwate, 020-8505, Japan. yishida@iwate-med.ac.jp.
Yoji
Y
Ishida
Iwate Medical University School of Medicine, Morioka, Japan.
Kazunori
K
Murai
Aomori Prefectural Central Hospital, Aomori, Japan.
Kohei
K
Yamaguchi
Kushiro Rosai Hospital, Kushiro, Japan.
Takuto
T
Miyagishima
Asahikawa Medical University School of Medicine, Asahikawa, Japan.
Motohiro
M
Shindo
Fukushima Medical University School of Medicine, Fukushima, Japan.
Kazuei
K
Ogawa
Kitami Red Cross Hospital, Kitami, Japan.
Takahiro
T
Nagashima
Okitama Public General Hospital, Higashi-Okitama, Japan.
Shinji
S
Sato
Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.
Reiko
R
Watanabe
Sapporo City General Hospital, Sapporo, Japan.
Satoshi
S
Yamamoto
Niigata Cancer Center Hospital, Niigata, Japan.
Takayuki
T
Hirose
Nihonkai General Hospital, Sakata, Japan.
Souich
S
Saitou
Hokkaido Cancer Center, Sapporo, Japan.
Masakatsu
M
Yonezumi
Hokkaido University School of Medicine, Sapporo, Japan.
Takeshi
T
Kondo
Yamagata University Faculty of Medicine, Yamagata, Japan.
Yuichi
Y
Kato
Meiji Pharmaceutical University, Kiyose, Japan.
Noboru
N
Mochizuki
Meiji Pharmaceutical University, Kiyose, Japan.
Keiko
K
Ohno
Meiji Pharmaceutical University, Kiyose, Japan.
Satoshi
S
Kishino
Aomori Prefectural Central Hospital, Aomori, Japan.
Kohmei
K
Kubo
Iwate Medical University School of Medicine, Morioka, Japan.
Tatsuo
T
Oyake
Iwate Medical University School of Medicine, Morioka, Japan.
Shigeki
S
Ito
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000069439:Dasatinib / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050736:Oncogene Protein v-crk / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D050736:Oncogene Protein v-crk; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib
Dasatinib; Half maximal inhibitory concentration; Molecular response; Phamacokinetics; Pharmacodynamics