EPID-12. Real-World Use of Medications With Moderate-to-Strong Cytochrome P450 3A4 (CYP3A4) Induction/Inhibition or Potential to Increase the Risk for Bleeding in Children and Adults with Neurofibromatosis Type 1-Associated Plexiform Neurofibroma (NF1-PN): A United States (US) Claims Database Analysis

Abstract BACKGROUND The FDA-approved MEK inhibitors for NF1-PN, mirdametinib (in children and adults) and selumetinib (in children), have distinct drug-drug interaction (DDI) profiles. Selumetinib is primarily metabolized by CYP3A4 and requires dose modifications when used concomitantly with CYP3A4 inhibitors/inducers. Mirdametinib is primarily metabolized by glucuronidation, oxidation via UGT and CES enzymes, and therefore does not require dose modifications when used concomitantly with CYP3A4 inhibitors/inducers. Selumetinib, containing vitamin E, may increase bleeding risk when combined with vitamin K antagonists and antiplatelet agents. METHODS A US claims database (data window: 01OCT2015-30SEP2024) was used to quantify the utilization of moderate-to-strong CYP3A4 inhibitors/inducers, vitamin K antagonists, and antiplatelet agents for patients with NF1-PN. The first PN diagnosis was identified as index, with a 1-year post-index (follow-up) continuous enrollment period to assess the utilization of these medications. RESULTS A total of 1114 children and 3415 adults with NF1-PN were eligible for this analysis (age at index, median [interquartile range]): children, 11 (7, 14) years; adults, 44 (31, 56) years. During follow-up, 9.6% (107/1114) of children and 19.4% (664/3415) of adults filled ≥1 prescription(s) for a moderate-to-strong CYP3A4 inducer or inhibitor. Additionally, 0.5% (6/1114) of children and 4.7% (159/3415) of adults filled ≥1 prescription(s) for vitamin K antagonists and antiplatelet agents. CONCLUSIONS The current analysis demonstrates the prevalent use of moderate-to-strong CYP3A4 inhibitors/inducers and medications that increase bleeding risk in children and adults with NF1-PN in the US. This highlights the importance of a thorough assessment of concomitant drugs prior to starting treatment with a MEK inhibitor. Mirdametinib and selumetinib (in children only) for NF1-PN treatment present with differentiated drug metabolism profiles. This should be carefully considered when treating with MEK inhibitors as potential DDIs could lead to lack of efficacy, undesirable toxicity, and/or increased risk of bleeding.