Gaining a Better Understanding for Safe Use of Ibrutinib

Chris Fausel, PharmD, MHA, BCOP, clinical manager at Indiana University Simon Cancer Center, breaks down practical considerations to ensure the safe use of ibrutinib with regard to concomitant medications and timely dose modifications.

Ibrutinib was the first agent approved by the FDA in the Bruton’s tyrosine kinase inhibitor drug class in 2013.  It is currently approved for use for chronic lymphocytic leukemia/small lymphocytic leukemia, mantle-cell non-Hodgkin lymphoma, marginal zone non-Hodgkin lymphoma, Waldenstrom’s macroglobinemia and chronic graft versus host disease in recipients of allogeneic hematopoietic stem cell transplant.

Given the expanding number of indications for the use of ibrutinib, there are a number of practical considerations to ensure the safe use of the drug with regard to concomitant medications and timely dose modifications.

Drug Interactions

Ibrutinib is metabolized primarily via CYP3A and to a minor extent by CYP2D6.  Drug-drug interaction studies suggest that co-administration with strong CYP3A inhibitors (e.g. ketoconazole) or moderate CYP3A4 inhibitors (e.g. erythromycin) can increase the ibrutinib AUC from 3 to 29 fold thereby increasing the risk of ibrutinib-associated toxicity.

CYP3A inducers (e.g. rifampin) can decrease the AUC of ibrutinib may decrease the ibrutinib AUC by 3 to 10 fold thereby comprising the efficacy of ibrutinib.

Ibrutinib and its primary metabolite PCI-45227 have not been shown to cause clinically meaningful inhibition or induction of CYP isoenzymes however they may inhibit P-gp and BCRP transport mechanisms that could impair clearance of drugs known to be impacted by these clearance mechanisms such as methotrexate and digoxin.

The manufacturer label recommends to avoid concomitant drug therapy known as strong CYP3A inhibitors and inducers in patients receiving ibrutinib.  Grapefruit and Seville oranges are also not recommended to be eaten for patients receiving ibrutinib due to their inhibitory activity on CYP3A.

Dose Modifications

In order to mitigate the risk associated with drug-drug interactions and adverse events associated with ibrutinib, the manufacturer recommends the following dose modifications:

Drug-Drug Interactions

Toxicity

References:

1.     https://imbruvica.com/files/prescribing-information.pdf.  Accessed October 25, 2019.

2.     deZwart L, Snoeys J, De Jong J, et al. Ibrutinib dosing strategies based on interaction potential of CYP3A4 perpetrators using physiologically based pharmacokinetic modeling.  Clin Pharmacol Ther 2016;100(5):548-57.

3.     Drug Interactions Flockhart Table.  https://drug-interactions.medicine.iu.edu/MainTable.aspx.  Accessed October 25, 2019.