1. Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI.
- Author
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Nicolson PLR, Hughes CE, Watson S, Nock SH, Hardy AT, Watson CN, Montague SJ, Clifford H, Huissoon AP, Malcor JD, Thomas MR, Pollitt AY, Tomlinson MG, Pratt G, and Watson SP
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase genetics, Agammaglobulinaemia Tyrosine Kinase metabolism, Agammaglobulinemia blood, Agammaglobulinemia genetics, Benzamides administration & dosage, Benzamides metabolism, Blood Platelets metabolism, Carrier Proteins administration & dosage, Genetic Diseases, X-Linked blood, Genetic Diseases, X-Linked genetics, Humans, Mutation, Peptides administration & dosage, Piperidines, Platelet Activation drug effects, Platelet Function Tests, Platelet Membrane Glycoproteins agonists, Protein Kinase Inhibitors metabolism, Pyrazines administration & dosage, Pyrazines metabolism, Pyrazoles administration & dosage, Pyrazoles metabolism, Pyrimidines administration & dosage, Pyrimidines metabolism, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Agammaglobulinemia drug therapy, Blood Platelets drug effects, Genetic Diseases, X-Linked drug therapy, Platelet Membrane Glycoproteins metabolism, Protein Kinase Inhibitors therapeutic use
- Abstract
Ibrutinib and acalabrutinib are irreversible inhibitors of Bruton tyrosine kinase used in the treatment of B-cell malignancies. They bind irreversibly to cysteine 481 of Bruton tyrosine kinase, blocking autophosphorylation on tyrosine 223 and phosphorylation of downstream substrates including phospholipase C-γ2. In the present study, we demonstrate that concentrations of ibrutinib and acalabrutinib that block Bruton tyrosine kinase activity, as shown by loss of phosphorylation at tyrosine 223 and phospholipase C-γ2, delay but do not block aggregation in response to a maximally-effective concentration of collagen-related peptide or collagen. In contrast, 10- to 20-fold higher concentrations of ibrutinib or acalabrutinib block platelet aggregation in response to glycoprotein VI agonists. Ex vivo studies on patients treated with ibrutinib, but not acalabrutinib, showed a reduction of platelet aggregation in response to collagen-related peptide indicating that the clinical dose of ibrutinib but not acalabrutinib is supramaximal for Bruton tyrosine kinase blockade. Unexpectedly, low concentrations of ibrutinib inhibited aggregation in response to collagen-related peptide in patients deficient in Bruton tyrosine kinase. The increased bleeding seen with ibrutinib over acalabrutinib is due to off-target actions of ibrutinib that occur because of unfavorable pharmacodynamics., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
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