| Abstract [eng] |
High-dose methotrexate is widely used in the treatment of pediatric leukemia. However, its pharmacokinetics shows considerable variability between patients, making it difficult to predict drug elimination and potential delays. To ensure treatment efficacy and reduce the risk of toxicity, it is important to evaluate factors influencing methotrexate pharmacokinetics. Aim of the thesis: To compare changes in high-dose methotrexate elimination parameters between 2008 and 2018 before and after the implementation of a standardized infusion protocol in children with leukemia using a population pharmacokinetic model. Task of the research: 1. To organize retrospective anonymized patient data on administered methotrexate infusions, post-infusion serum concentration changes, and laboratory and demographic parameters adapting them for population pharmacokinetic modeling. 2. To develop a population pharmacokinetic model that best describes the retrospective clinical data. 3. To identify and evaluate potential factors influencing methotrexate elimination. 4. To use the developed pharmacokinetic model to perform scenario simulations and assess the impact of modifications in the standardized infusion protocol and renal function parameters on methotrexate pharmacokinetics. Research methodology: An in silico population pharmacokinetic modeling study was performed using retrospective demographic and clinical data from 158 patients, including methotrexate blood concentrations measured at different time points after first infusion. Modeling was conducted using MonolixSuite 2021R2 software. Model performance was evaluated based on objective function values, goodness-of-fit plots, and visual predictive checks. Covariate analysis was performed systematically by adding each covariate to the model individually. The final population pharmacokinetic model was subsequently used for simulations. To evaluate the impact of the standardized high-dose methotrexate infusion protocol and creatinine increase on methotrexate elimination, different patient populations were simulated. Results and Conclusions: The systematically organized retrospective data were best described by a two-compartment population pharmacokinetic model with a proportional error model applied to clearance and the central compartment volume of distribution. Body weight was identified as the only statistically significant covariate affecting methotrexate clearance and the volume of distribution in the central compartment. However, additional covariates (acute lymphoblastic leukemia risk group, creatinine increase, standardized infusion protocol) were included in the final model as they improved the objective function values. Simulation results demonstrated that the implementation of the standardized protocol was associated with faster and more consistent methotrexate elimination, reduced variability in clearance, and a lower probability of toxic concentrations. In contrast, increased creatinine levels were associated with slower drug elimination and a higher risk of toxic methotrexate concentrations. No statistically significant differences were observed when comparing pharmacokinetic parameters between simulated patient groups before and after the implementation of the standardized infusion protocol (CL p = 0.8545, V1 p = 0.798). Similarly, no statistically significant differences were found when comparing pharmacokinetic parameters across different creatinine elevation groups (CL p = 0.7499, V1 p = 0.9934). The results obtained from the analysis of first infusion data suggest a trend towards faster methotrexate elimination following the implementation of the standardized infusion protocol, compared to simulated patients prior its introduction. |
