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Published on: July 19, 2024
Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical
Feng R Luo1, Zheng Yang, Amy Camuso
1Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA. roger.luo@bms.com
Purpose:
Chronic myeloid leukemia (CML) is caused by reciprocal translocation between chromosomes 9 and 22, forming BCR-ABL, a constitutively activated tyrosine kinase. Imatinib mesylate, a selective inhibitor of BCR-ABL, represents current frontline therapy for CML; however, emerging evidence suggests that drug resistance to imatinib may limit its long-term success. To improve treatment options, dasatinib (BMS-354825) was developed as a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases. To date, dasatinib has shown promising anti-leukemic activity in preclinical models of CML and in phase I/II clinical studies in patients with imatinib-resistant or imatinib-intolerant disease.
Experimental Design:
The pharmacokinetic and pharmacodynamic biomarkers of dasatinib were investigated in K562 human CML xenografts grown s.c. in severe combined immunodeficient mice. Tumoral levels of phospho-BCR-ABL/phospho-CrkL were determined by Western blot.
Results:
Following a single oral administration of dasatinib at a preclinical efficacious dose of 1.25 or 2.5 mg/kg, tumoral phospho-BCR-ABL/phospho-CrkL were maximally inhibited at approximately 3 hours and recovered to basal levels by 24 hours. The time course and extent of the inhibition correlated with the plasma levels of dasatinib in mice. Pharmacokinetic/biomarker modeling predicted that the plasma concentration of dasatinib required to inhibit 90% of phospho-BCR-ABL in vivo was 10.9 ng/mL in mice and 14.6 ng/mL in humans, which is within the range of concentrations achieved in CML patients who responded to dasatinib treatment in the clinic.
Conclusions:
Phospho-BCR-ABL/phospho-CrkL are likely to be useful clinical biomarkers for the assessment of BCR-ABL kinase inhibition by dasatinib.
Insights
Dasatinib effectively inhibits BCR-ABL kinase in preclinical models of chronic myeloid leukemia (CML). This study validates phospho-BCR-ABL/phospho-CrkL as biomarkers for assessing dasatinib
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Chronic myeloid leukemia (CML) is driven by the BCR-ABL tyrosine kinase.
- Imatinib resistance necessitates novel therapeutic strategies.
- Dasatinib is a multi-targeted kinase inhibitor for CML treatment.
Purpose of the Study:
- To investigate the pharmacokinetics and pharmacodynamics of dasatinib.
- To assess tumoral BCR-ABL kinase inhibition by dasatinib.
- To identify predictive biomarkers for dasatinib efficacy.
Main Methods:
- K562 CML xenografts in immunodeficient mice were used.
- Dasatinib pharmacokinetics were analyzed.
- Tumoral phospho-BCR-ABL/phospho-CrkL levels were measured by Western blot.
Main Results:
- Oral dasatinib (1.25-2.5 mg/kg) maximally inhibited phospho-BCR-ABL/phospho-CrkL within 3 hours.
- Inhibition correlated with plasma dasatinib concentrations.
- Predicted effective concentrations in humans align with clinical response levels.
Conclusions:
- Phospho-BCR-ABL and phospho-CrkL are reliable biomarkers for dasatinib's BCR-ABL kinase inhibition.
- These biomarkers can guide clinical assessment of dasatinib treatment.
- Dasatinib demonstrates promising activity in preclinical CML models.
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