William G. Wierda

Ibrutinib is a selective and irreversible inhibitor of Bruton's tyrosine kinase (BTK) that entered phase 1 clinical trials in 2009 based on preclinical efficacy in models of B-cell malignancy and autoimmune disease.[1, 2] The initial phase 1 trial showed clear efficacy in a number of lymphoid malignancies at doses as low as 1.25 mg/kg/d. Furthermore, full receptor occupancy was demonstrated at 2.5 mg/kg/d. Despite these pharmacological and early clinical findings, development of ibrutinib continued at doses of 420 mg qd and 560 mg qd, levels 3-4 fold higher than suggested by the pharmacological data. In addition, the absorption of ibrutinib is enhanced by administration of food, which may explain why even the lowest dose showed efficacy in some patients.