Pharmacokinetics and Pharmacodynamics of Glucarpidase Rescue Treatment After High-dose Methotrexate Therapy Based on Modeling and Simulation

Background: Model-informed approaches are important in drug development, including for dose optimization and the collection of evidence in support of efficacy.

Materials and methods: We developed a modified Michaelis-Menten pharmacokinetics/pharmacodynamics model and used it to conduct simulations of glucarpidase at doses between 10 and 80 U/kg rescue treatment after high-dose methotrexate therapy. We carried out a dose-finding modeling and simulation study before a phase II study of glucarpidase. Monte-Carlo simulations were conducted using the deSolve package of R software (version 4.1.2). The proportion of samples in which the plasma methotrexate concentration was less than 0.1 and 1.0 μmol/l at 70 and 120 h after methotrexate treatment was evaluated for each dosage of glucarpidase.

Results: The proportion of samples in which the plasma methotrexate concentration was less than 0.1 μmol/l at 70 h after methotrexate treatment was 71.8% and 89.6% at 20 and 50 U/kg of glucarpidase, respectively. The proportion of samples in which the plasma methotrexate concentration was less than 0.1 μmol/l at 120 h after methotrexate treatment was 46.4% and 59.0% at 20 and 50 U/kg of glucarpidase, respectively.

Conclusion: We determined a recommended glucarpidase dose of 50 U/kg to be ethically acceptable. A rebound in the serum concentration of methotrexate may be observed in many patients after the administration of glucarpidase, and long-term monitoring (over 144 h) of the serum methotrexate concentration may be needed after the administration of glucarpidase. Its validity was confirmed in the phase II study and glucarpidase was approved for manufacturing in Japan.