Graduate Student University of Iowa Iowa City, Iowa, United States
Background: Methotrexate (MTX) is an important therapy for treating many types of lymphoid malignancies, including Primary Central Nervous System Lymphoma (PCNSL). It is widely acknowledged that the pharmacokinetics (PK) information of MTX is important as it ties closely to both MTX’s anticancer efficacy as well as its adverse effects. Although numerous population PK (PopPK) studies for MTX are available in the literature, there is limited PopPK reports to characterize MTX PK in PCNSL patients. The goal of our study was to build a PopPK model to characterize MTX disposition, to assess the sources of MTX PK variability and to help in decision making for MTX dosing in PCNSL patients. Methods: MTX PK data from 41 PCNSL patients with a combined total of 1291 plasma samples were obtained at the University of Iowa Hospital and Clinics. PopPK analysis was performed using a nonlinear mixed-effects modeling approach with NONMEM software interfaced with Pirana. First-order conditional estimation method with interaction and user-defined subroutine (ADVAN13) were used to estimate the population mean values of the PK parameters, interindividual variability, and residual variability. Results: Among the various models evaluated, a three-compartment model with linear elimination was best for characterizing the MTX PK data. Among the covariates tested, BSA had a significant effect on the volume of distribution (Vd) and was included in the final model. The clearance of MTX was estimated to be 4.52 L/h and the Vd was 17 L for the central compartment which are consistent with the literature reports. Conclusion: A PopPK model was successfully established to describe MTX PK in PCNSL patients. The results of this model will provide guidance in clinical practice for selection of the appropriate dose of MTX in PCNSL patients.
