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.
Highlights
High-dose methotrexate (HD-MTX, ≥ 1 g m−2) is the base therapy for the treatment of various lymphoid malignancies, such as acute lymphoblastic leukemia (Sakura et al, 2018) and non-Hodgkin’s lymphoma (Reiter et al, 1999), especially for treating primary or secondary central nervous system lymphoma (Plotkin et al, 2004; Zhu et al, 2009)
Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F
Patients experiencing delayed MTX elimination have been reported to be at an elevated risk of toxicity, such as nephrotoxicity, myelotoxicity, mucositis, neurological complications, and other adverse effects, which may lead to significant morbidity and delays in treatment (Howard et al, 2016)
Summary
High-dose methotrexate (HD-MTX, ≥ 1 g m−2) is the base therapy for the treatment of various lymphoid malignancies, such as acute lymphoblastic leukemia (Sakura et al, 2018) and non-Hodgkin’s lymphoma (Reiter et al, 1999), especially for treating primary or secondary central nervous system lymphoma (Plotkin et al, 2004; Zhu et al, 2009). Only 10% of MTX is excreted as unchanged drug in the bile, whereas the majority is eliminated as unchanged drug through the kidneys within 24 h (Csordas et al, 2013). Patients experiencing delayed MTX elimination have been reported to be at an elevated risk of toxicity, such as nephrotoxicity, myelotoxicity, mucositis, neurological complications, and other adverse effects, which may lead to significant morbidity and delays in treatment (Howard et al, 2016). To prevent this systemic toxicity, supportive care, such as fluid hydration, urine alkalinization, and leucovorin rescue, is conducted as HD-MTX is administered (Widemann and Adamson, 2006). Post-dose therapeutic drug monitoring is routinely performed to maintain MTX plasma concentrations within the cytotoxic range for leukemic cells and, below those associated with toxicity (Wall et al, 2000; Paci et al, 2014)
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