TY - JOUR
T1 - Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia
AU - Yoshimura, Satoshi
AU - Panetta, John C.
AU - Hu, Jianzhong
AU - Li, Lie
AU - Gocho, Yoshihiro
AU - Du, Guoqing
AU - Umezawa, Akihiro
AU - Karol, Seth E.
AU - Pui, Ching Hon
AU - Mullighan, Charles G.
AU - Konopleva, Marina
AU - Stock, Wendy
AU - Teachey, David T.
AU - Jain, Nitin
AU - Yang, Jun J.
N1 - Funding Information:
We thank the Hartwell Center for Biotechnology, the Flow Cytometry and Cell Sorting Core, and the Animal Research Center at St. Jude Children’s Research Hospital for their technical assistance. We also thank all the patients and families for donating research specimens, as well as the clinicians and research staff for assistance in sample collection. This work was in part supported by the National Institutes of Health (P30CA21765, R01CA264837, and U01CA264610), American Lebanese Syrian Associated Charities, the Translational Research Program at the Leukemia & Lymphoma Society (6665-23), and the Takeda Pharmaceutical Company.
Funding Information:
We thank the Hartwell Center for Biotechnology, the Flow Cytometry and Cell Sorting Core, and the Animal Research Center at St. Jude Children’s Research Hospital for their technical assistance. We also thank all the patients and families for donating research specimens, as well as the clinicians and research staff for assistance in sample collection. This work was in part supported by the National Institutes of Health (P30CA21765, R01CA264837, and U01CA264610), American Lebanese Syrian Associated Charities, the Translational Research Program at the Leukemia & Lymphoma Society (6665-23), and the Takeda Pharmaceutical Company.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/6
Y1 - 2023/6
N2 - LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent. Given orally in mice, ponatinib was associated with slower clearance with a longer Tmax and higher AUC0-24 h, although maximum pLCK inhibition was comparable between the two drugs. After establishing the exposure-to-response models, we simulated the steady-state pLCK inhibitory effects of each drug at currently approved dosages in humans: dasatinib at 140 mg and ponatinib at 45 mg once daily are both sufficient to achieve >50% pLCK inhibition for 13.0 and 13.9 h/day, respectively, comparable to pharmacodynamic profiles of these agents in BCR::ABL1 leukemias. Moreover, we developed a dasatinib-resistant T-ALL cell line model with LCK T316I mutation, in which ponatinib retained partial activity against LCK. In conclusion, we described the pharmacokinetic and pharmacodynamic profiles of dasatinib and ponatinib as LCK inhibitors in T-ALL, providing critical data for the development of human trials of these agents.
AB - LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent. Given orally in mice, ponatinib was associated with slower clearance with a longer Tmax and higher AUC0-24 h, although maximum pLCK inhibition was comparable between the two drugs. After establishing the exposure-to-response models, we simulated the steady-state pLCK inhibitory effects of each drug at currently approved dosages in humans: dasatinib at 140 mg and ponatinib at 45 mg once daily are both sufficient to achieve >50% pLCK inhibition for 13.0 and 13.9 h/day, respectively, comparable to pharmacodynamic profiles of these agents in BCR::ABL1 leukemias. Moreover, we developed a dasatinib-resistant T-ALL cell line model with LCK T316I mutation, in which ponatinib retained partial activity against LCK. In conclusion, we described the pharmacokinetic and pharmacodynamic profiles of dasatinib and ponatinib as LCK inhibitors in T-ALL, providing critical data for the development of human trials of these agents.
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U2 - 10.1038/s41375-023-01900-5
DO - 10.1038/s41375-023-01900-5
M3 - Article
C2 - 37076694
AN - SCOPUS:85153032818
SN - 0887-6924
VL - 37
SP - 1194
EP - 1203
JO - Leukemia
JF - Leukemia
IS - 6
ER -