Risk of Major Bleeding with Ibrutinib

Mock, J.N.; Kunk, Paul R.; Palkimas, Surabhi; Sen, Jeremy; Devitt, Michael; Horton, Bethany J.; Portell, Craig A.; Williams, Michael E.; Maitland, Hillary S.

doi:10.1016/j.clml.2018.07.287

Cited by 54 publications

(46 citation statements)

References 19 publications

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“…Current studies suggest that there is an overall increased risk of bleeding, with no significant risk of lifethreatening hemorrhage compared to the general population [9]. However, a more recent retrospective study evaluating the risk of major bleeding in patients on ibrutinib found that this may be higher than previously thought, especially in the setting of concurrent antiplatelet or anticoagulant use [10].…”

Section: Discussionmentioning

confidence: 92%

Ibrutinib-Associated Cardiac Tamponade with Concurrent Antiplatelet Therapy

Miatech

Hughes

McCarty

et al. 2020

Case Reports in Hematology

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Ibrutinib is approved for the first-line treatment of chronic lymphocytic leukemia (CLL). A well-known side effect of ibrutinib therapy is increased bleeding risk, which ranges from mild mucocutaneous bleeding to rarely life-threatening hemorrhage. e increased bleeding tendency associated with ibrutinib is thought to be related to its effect on several platelet signaling pathways, which can be exacerbated in the setting of concurrent antiplatelet or anticoagulant therapy. We present an 82-year-old male with CLL on ibrutinib and concurrent antiplatelet therapy who developed cardiac tamponade due to a hemorrhagic pericardial effusion requiring emergent placement of a pericardial window. is case further highlights the risk of major bleeding in patients treated with ibrutinib and concurrent antiplatelet therapy.

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Section: Discussionmentioning

confidence: 92%

Ibrutinib-Associated Cardiac Tamponade with Concurrent Antiplatelet Therapy

Miatech

Hughes

McCarty

et al. 2020

Case Reports in Hematology

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“…The recent high interest in understanding kinase selectivity profiles of various BTK inhibitors stems from a desire to optimize patient outcomes with treatment, minimize adverse events, and understand how off-target effects may be related to such events. For example, bleeding is an adverse event observed in patients treated with BTK inhibitors, with most cases being grade 1 or 2 in severity (Mock et al, 2018). Although clinical data were still being accumulated, an earlier hypothesis based on kinase affinity data proposed that acalabrutinib might lead to lower bleeding rates because of its higher selectivity for BTK relative to TEC (Byrd et al, 2016;Barf et al, 2017;Awan et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Relative Selectivity of Covalent Inhibitors Requires Assessment of Inactivation Kinetics and Cellular Occupancy: A Case Study of Ibrutinib and Acalabrutinib

Hopper

Gururaja

Kinoshita

et al. 2019

J Pharmacol Exp Ther

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Kinases form an attractive class of targets for small molecule inhibitors, but similarity among their adenosine triphosphate binding sites presents difficulties for developing selective drugs. Standard methods of evaluating selectivity of most reversibly bound drugs account for binding affinity but not the two-step process, affinity and inactivation, occurring during covalent inhibition. To illustrate this concept, we assessed the selectivity of Bruton's tyrosine kinase (BTK) over TEC kinases by two novel therapeutics: ibrutinib and acalabrutinib. The two-step process and time-dependent inhibition unique to covalent inhibitors were evaluated with two biochemical assays measuring enzymatic function and inhibition kinetics. The selectivity for BTK over TEC found in these biochemical analyses was 1-1.5 for ibrutinib and 3.0-4.2 for acalabrutinib. To further assess drug selectivity in a more physiologically relevant context, we developed cellbased occupancy assays that quantify the percentage of druginactivated kinases. Cellular selectivity of BTK over TEC was determined after MWCL-1 cells, and samples from patients with chronic lymphocytic leukemia (CLL) were treated for durations and concentrations based on human pharmacokinetics of each drug. In MWCL-1 cells, BTK/TEC selectivities measured at 0.5, 1, and 3 hours were 2.53, 1.05, and 1.51 for ibrutinib and 0.97, 1.13, and 2.56 for acalabrutinib, respectively. The equivalent selectivity measured in samples from patients with CLL were 1.31 6 0.27 and 1.09 6 0.11 for ibrutinib and acalabrutinib, respectively. Collectively, our data show that when properly accounting for time-dependent factors and relevant cellular context, ibrutinib and acalabrutinib demonstrate similar selectivity for BTK over TEC. SIGNIFICANCE STATEMENT This study shows relative selectivity of covalent inhibitors toward different kinase targets should be assessed with both affinity and inactivation kinetics to accurately account for time-dependent effects of covalent binding and assessed in a cellular matrix to reproduce the physiologic context of target inhibition. This is illustrated with a case study of ibrutinib and acalabrutinib for which selectivity assessment with appropriate assays, as opposed to measuring binding affinity with KINOMEscan alone, corroborate emerging clinical data demonstrating similar safety profiles between the therapies.

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“…In a retrospective study of 616 patients with CLL, 41% of the patients discontinued ibrutinib, with intolerance rather than CLL progression being the major cause of discontinuation . In another recent retrospective analysis, major bleeding occurred in 19% of patients receiving ibrutinib . Inhibition of other kinases than BTK has been suggested to be involved in some of these adverse effects, such as inhibitory effect on platelet function .…”

Section: Discussionmentioning

confidence: 99%

“…26 In another recent retrospective analysis, major bleeding occurred in 19% of patients receiving ibrutinib. 27 Inhibition of other kinases than BTK has been suggested to be involved in some of these adverse effects, such as inhibitory effect on platelet function. 28 Based on our present results, the concomitant use of currently available 70-mg and 140-mg capsules of ibrutinib with itraconazole or other strong CYP3A4 inhibitors increases ibrutinib exposure to a higher level than what is observed when the usual 420-mg or 560-mg daily doses are taken without CYP3A4 inhibitors.…”

Section: Itraconazole Increases Ibrutinib Exposurementioning

confidence: 99%

Itraconazole Increases Ibrutinib Exposure 10‐Fold and Reduces Interindividual Variation—A Potentially Beneficial Drug‐Drug Interaction

Tapaninen

Olkkola

Tornio

et al. 2019

Clinical Translational Sci

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The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first‐pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2–4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose‐adjusted geometric mean area under the concentration‐time curve from zero to infinity (AUC0–∞) of ibrutinib 10.0‐fold (90% confidence interval (CI) 7.2–13.9; P < 0.001) and peak plasma concentration (Cmax) 8.8‐fold (90% CI 6.3–12.1; P < 0.001). During itraconazole, the intersubject variation for the AUC0–∞ (55%) and Cmax (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.

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Risk of Major Bleeding with Ibrutinib

Cited by 54 publications

References 19 publications

Ibrutinib-Associated Cardiac Tamponade with Concurrent Antiplatelet Therapy

Ibrutinib-Associated Cardiac Tamponade with Concurrent Antiplatelet Therapy

Relative Selectivity of Covalent Inhibitors Requires Assessment of Inactivation Kinetics and Cellular Occupancy: A Case Study of Ibrutinib and Acalabrutinib

Itraconazole Increases Ibrutinib Exposure 10‐Fold and Reduces Interindividual Variation—A Potentially Beneficial Drug‐Drug Interaction

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