The effect of food on the pharmacokinetics of oral

Authors: Jan de Jong Juthamas Sukbuntherng Donna Skee Joe Murphy Susan O’Brien John C Byrd Danelle James Peter Hellemans David J Loury Juhui Jiao Vijay Chauhan Erik Mannaert

Publish Date: 2015/02/28

Volume: 75, Issue: 5, Pages: 907-916

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Abstract

Three studies were analyzed Study 1 was a randomized openlabel singledose fourway crossover study in 44 healthy participants Study 2 was a randomized repeatdose crossover study in 16 patients with previously treated chronic lymphocytic leukemia CLL Ibrutinib dose was 420 mg in both studies Study 3 was an openlabel sequential study to assess the effect of a standard breakfast on ibrutinib 560 mg in eight healthy participantsAdministration of singledose ibrutinib under fasting conditions study 1 resulted in approximately 60  of exposure compared with drug intake either 30 min before 30 min after fed or 2 h after a highfat meal Similar food effect was observed study 3 when ibrutinib was given 30 min before meal In CLL patients study 2 the C max and AUC under fasting conditions were 43 and 61  respectively relative to fed conditions When administered oncedaily in uncontrolled foodintake conditions ≥30 min before or 2 h after exposures were slightly ≈30  lower than in fed condition When corrected for repeated dosing pharmacokinetic parameters in healthy participants and patients were comparable Ibrutinib was generally well tolerated in all settings studiedIbrutinib administered in fasted condition reduces exposure to approximately 60  as compared with dosing in proximity to foodintake regardless of timing/type of meal Because repeated drug intake in fasted condition is unlikely no food restrictions may be needed to administer ibrutinibIbrutinib Imbruvica® was recently approved in the USA and European Union for the treatment of previously treated chronic lymphocytic leukemia CLL 1 and mantle cell lymphoma MCL 2 in patients who have had at least one prior therapy The most common type of leukemia in the Western world is CLL and has a mean onset between 65 and 75 years of age It is characterized by an accumulation of mature B cells in the blood lymph nodes and bone marrow 3 There were an estimated 15680 new cases of CLL among the 69740 newly diagnosed nonHodgkin’s lymphoma cases in the USA in 2013 4 Another form of nonHodgkin’s lymphoma is MCL which is difficult to treat and leaves patients with a poor prognosis 2 5 Cytotoxic chemotherapeutic agents are often used to treat B cell malignancies and although survival may be improved the disease is not curative 6 Patients must be able to tolerate the side effects and toxicities associated with these agents and of particular concern myelotoxic effects which increases the risk of opportunistic infections With existing frontline treatments involving multiagent chemoimmunotherapy regimens disease resistance to treatment is common in patients with relapse A phase III study RESONATE in previously treated CLL patients demonstrated ibrutinib treatment reduced the risk of progression or death by 78  compared to the CD20directed monoclonal antibody ofatumumab 7 The safety profile was acceptable with no increase in the risk of grade 3/4 adverse events AEs with ibrutinib Furthermore despite advances most patients with CLL and MCL die of their disease 2 8 9 Therefore novel therapies are needed for improved medical treatment for these malignant diseasesMany factors contribute to the viability of B cells and their development proliferation and survival including Bcell receptor BCR activation and signaling 10 The BCR signaling is a key factor in the survival of B cell malignancies 11 12 13 Although the exact mechanism by which BCR regulates B cell activity is unknown BCR activation is mediated via a cascade of enzymatic activity among which is an essential kinase enzyme Bruton’s tyrosine kinase BTK 14 15 Bruton’s tyrosine kinase is expressed in all hematopoietic cells with the exception of T lymphocytes and natural killer cells 16 Dysfunctional BTK due to mutations leads to an inherited disease Xlinked agammaglobulinemia in which patients lack peripheral mature B cells have increased serum immunoglobulin and are more susceptible to infection 16 17 Therefore it is reasonable to target BTK to inhibit survival and proliferation of malignant B cellsPreclinical studies have demonstrated that ibrutinib inhibits several processes including survival proliferation adhesion and tumor cell migration 18 19 20 Inhibition of BTK is a novel mechanism to treat nonHodgkin’s lymphoma and ibrutinib does this by forming an irreversible covalent bond with BTK at the Cys 481 site In early studies ibrutinib as a single agent demonstrated high response rates and durable efficacy in previously treated B cell malignancies 1 2 21

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