Ibrutinib, but not zanubrutinib, induces platelet receptor shedding of GPIb-IX-V complex and integrin alpha(IIb)beta(3) in mice and humans
BLOOD ADVANCES
Authors: Dobie, Gasim; Kuriri, Fand A.; Omar, Musab M. A.; Alanazi, Fehaid; Gazwani, Ali M.; Tang, Chloe P. S.; Sze, Daniel Man-yuen; Handunnetti, Sasanka M.; Tam, Constantine; Jackson, Denise E.
Abstract
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has proven to be efficacious in the treatment of B-cell chronic lymphocytic leukemia (B-CLL) and related diseases. However, a major adverse side effect of ibrutinib is bleeding, including major hemorrhages. The bleeding associated with ibrutinib use is thought to be due to a combination of on-target irreversible Btk inhibition, as well as off-target inhibition of other kinases, including EGFR, ITK, JAK3, and Tec kinase. In this study, we investigated the effects of ibrutinib vs zanubrutinib (a more selective Btk inhibitor) on platelet activation, glycoprotein expression, and thrombus formation. Ibrutinib, but not zanubrutinib, induced a time- and dose-dependent shedding of GPIb-IX complex and integrin alpha(IIb)beta(3), but not of GPVI and GPV, from the platelet surface. The shedding of GPIb alpha and GPIX was blocked by GM6001 and TAPI-2, an ADAM17 inhibitor but not ADAM10 inhibitor. Ibrutinib but not zanubrutinib treatment of human platelets increased ADAM17 activation. Pretreatment of C57BL/6 mice with ibrutinib (10 mg/kg), but not zanubrutinib (10 mg/kg), inhibited ex vivo and in vivo thrombus growth over time. Platelets from ibrutinib-treated patients with CLL showed reduced GPIb-IX complex and integrin alpha(IIb)beta(3) surface expression and reduced ex vivo thrombus formation under arterial flow, which was not observed in zanubrutinib-treated patients. In mice, ibrutinib, but not zanubrutinib, led to increased soluble GPIb alpha and soluble alpha(IIb) levels in plasma. These data demonstrate that ibrutinib induces shedding of GPIb alpha and GPIX by an ADAM17-dependent mechanism and integrin alpha(IIb)beta(3) by an unknown sheddase, and this process occurs in vivo to regulate thrombus formation.
Drug interactions with Bruton's tyrosine kinase inhibitors: clinical implications and management
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Authors: Fancher, Karen M.; Pappacena, Jeremy J.
Abstract
Bruton's tyrosine kinase (BTK) plays an essential role in B-cell development, differentiation and B-cell receptor (BCR) signaling. The use of Bruton's tyrosine kinase inhibitors (BTKi) in the treatment of lymphoid malignancies has dramatically increased, owing to both impressive efficacy and ease of administration. However, BTKi have a range of drug-drug and drug-food interactions, which may alter drug efficacy and/or increase toxicity. Healthcare professionals should be aware of the probability of drug interactions with BTKi and make recommendations accordingly. In this article, we discuss the relevant drug-drug and drug-food interactions associated with ibrutinib, acalabrutinib, and zanubrutinib, and provide clinical practice recommendations for managing these interactions based on the available literature.
COA
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