Evaluation and Application of Population Pharmacokinetic Models for Identifying Delayed Methotrexate Elimination in Patients With Primary Central Nervous System Lymphoma

Abstract

Objective: Several population pharmacokinetic (popPK) models have been developed to determine the sources of methotrexate (MTX) PK variability. It remains unknown if these published models are precise enough for use or if a new model needs to be built. The aims of this study were to 1) assess the predictability of published models and 2) analyze the potential risk factors for delayed MTX elimination.Methods: A total of 1458 MTX plasma concentrations, including 377 courses (1–17 per patient), were collected from 77 patients who were receiving high-dose MTX for the treatment of primary central nervous system lymphoma in Huashan Hospital. PopPK analysis was performed using the NONMEM® software package. Previously published popPK models were selected and rebuilt. A new popPK model was then constructed to screen potential covariates using a stepwise approach. The covariates were included based on the combination of theoretical mechanisms and data properties. Goodness-of-fit plots, bootstrap, and prediction- and simulation-based diagnostics were used to determine the stability and predictive performance of both the published and newly built models. Monte Carlo simulations were conducted to qualify the influence of risk factors on the incidence of delayed elimination.Results: Among the eight evaluated published models, none presented acceptable values of bias or inaccuracy. A two-compartment model was employed in the newly built model to describe the PK of MTX. The estimated mean clearance (CL/F) was 4.91 L h−1 (relative standard error: 3.7%). Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F. The median and median absolute prediction errors of the final model were -10.2 and 36.4%, respectively. Results of goodness-of-fit plots, bootstrap, and prediction-corrected visual predictive checks indicated the high predictability of the final model.Conclusions: Current published models are not sufficiently reliable for cross-center use. The elderly patients and those with renal dysfunction, hypoalbuminemia are at higher risk of delayed elimination.

External Evaluation of Population Pharmacokinetic Models for High‐Dose Methotrexate in Adult Patients with Hematological Tumors

“…The model proposed by Mao et al showed superior accuracy (MDPE 19.25%), but did not meet the other standard. 9 For other evaluation indicators, none of the models met all the criteria (MDPE% ≤ ±20%, MAPE% ≤ 30%, F 20 ≥ 35%, and F 30 ≥ 50%). B-A plots of the population prediction showed that all models exhibited an apparent trend of undervaluation (Figure 1), with a mean range of −102.8% to −24.28%.…”

“…In a recent article, 8 previously published models for HDMTX in adults were validated using goodness of fit (GOF) and VPCs. 9 We validated a total of 7 models, with 4 of them overlapping with those in the aforementioned article. The remaining 3 models had not been previously validated.…”

“…Seven eligible popPK studies were identified for further analysis during the literature review. 4,7,9,17,[19][20][21] The screening process is presented in Appendix S1.…”

“…4 Delayed MTX elimination may expose patients to a serious risk of toxicity, such as myelotoxicity, nephrotoxicity, mucositis, and other adverse effects, which can cause treatment delays. 9 To prevent the systemic toxicity associated with HDMTX administra-tion, supportive care measures are typically employed in clinical practice. These measures may include fluid hydration, urine alkalinization, and rescue therapy with leucovorin (folinic acid).…”

“…Delayed MTX elimination is defined as plasma MTX concentrations remaining above 50 µmol/L at 24 hours or above 5 µmol/L at 48 hours after administration 4 . Delayed MTX elimination may expose patients to a serious risk of toxicity, such as myelotoxicity, nephrotoxicity, mucositis, and other adverse effects, which can cause treatment delays 9 . To prevent the systemic toxicity associated with HDMTX administration, supportive care measures are typically employed in clinical practice.…”