PII-064 - DRUG-DRUG INTERACTION MODEL DESCRIBES HIGH-DOSE METHOTREXATE PHARMACOKINETICS AFTER GLUCARPIDASE RESCUE

Z. Taylor¹, N. Punt², T. Mizuno³, L. Ramsey⁴; ¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, ²Medimatics, Maastricht, The Netherlands, ³Cincinnati Children's Hospital, Cincinnati, OH, United States, ⁴Children's Mercy, Kansas City, MO, United States.

Background: Glucarpidase (GLU) is an exogenous enzyme that is intravenously administered at 50 units/kg to rescue from high-dose methotrexate (HDMTX) overdose by rapidly metabolizing plasma methotrexate (MTX) into inactive metabolites. MTXPK.org is a free clinical decision support tool that facilitates optimal use of GLU using real-time patient data but cannot describe the PK of high-dose methotrexate (HDMTX) post-GLU. Interference by these inactive metabolites complicates the use of immunoassays for therapeutic drug management of HDMTX. Therefore, this study aims to develop a drug-drug interaction (DDI) model that describes the PK of HDMTX following GLU administration.

Methods: Edsim++ (Medimatics), an object-oriented PKPD solver, was used to construct the DDI model. The 3-compartment structural model used by MTXPK.org was selected to describe the PK of HDMTX 1 and uses body surface area and serum creatinine to inform estimated clearance. A GLU model was constructed following the published PK parameters from the FDA label 2 where GLU is systemically cleared at 7.5 mL/min with a volume of 3.6 L. Simulations were performed for a virtual patient (BSA of 1.73 m2, a weight of 70 kg, serum creatinine of 0.6 mg/dL) receiving a 5 g/m2 MTX dose over 24-hours with a 3,500 unit dose of GLU administered 42 hours after the start of the HDMTX infusion.

Results: The MTX-GLU DDI model was constructed using an ‘effector’ object in Edsim++ that linked the HDMTX model with the GLU model by creating an alternative route of elimination when GLU is present. Simulations indicate a 70% reduction in MTX concentration 15 minutes post GLU administration, with a 95% reduction achieved within 38 minutes (Figure). A small rebound effect caused by redistribution of peripheral MTX was observed and is consistent with the GLU consensus guideline3.

Conclusion: The MTX-GLU DDI model has the potential to describe the PK of HDMTX following GLU administration. Integrating this model into MTXPK.org will enhance real-time model-informed decision making. Additional modeling and simulation across diverse doses of HDMTX, body sizes, and renal function are needed.