High dose methotrexate population pharmacokinetics and Bayesian estimation in patients with lymphoid malignancy

Abstract

The purpose of present study was to develop a population pharmacokinetic model of high dose methotrexate (HD-MTX) infusion in patients with lymphoid malignancy, to investigate the biological and clinical covariates related to the drug distribution and elimination. It is also the purpose to propose a limited sampling strategy (LSS) for the estimation of the time above the threshold (0.2 micromol.L(-1)). A total 82 patients with lymphoid malignancy were involved in the study. A pharmacokinetic model was developed using nonlinear mixed-effect model. The influence of demographic characteristics, biological factors, and concurrent administration were investigated. The final predictive performance was validated by bootstrap and cross-validation. Bayesian estimation was evaluated. The pharmacokinetics of HD-MTX was described by a two-compartment model. The pharmacokinetic parameters and the inter-individual variability were as follows: the clearance CL, 7.45 L.h(-1) (inter-individual variability 50.6%), the volume of the central and peripheral compartment V(1), 25.9 L (22.5%), V(2), 9.23 L (97.8%), respectively, and the intercompartmental clearance Q, 0.333 L.h(-1) (70.4%). The influence of serum creatinine on CL and weight on V(1) was retained in the final model. The protocol involved one sampling time at 44 h after the start of the infusion, allowing one to predict the time at which the MTX concentration reached the expected threshold (0.2 micromol.L(-1)). Serum creatinine and weight showed significant influence on methotrexate CL and V(1), respectively. Furthermore, a Bayesian estimation based on the covariates and 44 h sample was developed, allowing prediction of the individual methotrexate pharmacokinetic parameters and the time to 0.2 micromol.L(-1).

Developing Population Pharmacokinetic Parameters for High-Dose Methotrexate Therapy: Implication of Correlations among Developed Parameters for Individual Parameter Estimation Using the Bayesian Least-Squares Method

“…This pair of parameters had been included in most of the previously reported population parameters. 9,[11][12][13][14][15][16][17][18][19] This result indicates that the reported population parameters may be inappropriate for the Bayesian least-squares method used in the present study. Thus, we compared correlations among the possible combinations of population parameters.…”

“…The former was the combination that had the weakest correlations in the present study, and the latter was the most frequently reported combination in previous studies. [9][10][11][12][13][14][15][16][17][18][19] As shown above, the sum of the absolute value of correlation coefficients among V 1 , k 10 , k 12 , and k 21 was 1.05 for regimen B, whereas V 1 , V 2 , CL, and Q was 3.29 for regimen B. Because of the relatively strong correlations among V 1 , V 2 , CL, and Q, this combination of the population parameters was considered to be a good target for a comparison with V 1 , k 10 , k 12 , and k 21 .…”

“…Several population parameters have already been developed for cases receiving HD-MTX, and the usefulness of these parameters has been tested. [9][10][11][12][13][14][15][16][17][18][19] Many of these studies were performed using NONMEM, which has been used as the standard method for population pharmacokinetic analyses including Bayesian estimation. However, this software is rarely used in clinical settings because of the difficulties associated with its use.…”

“…In addition, because an increase in the parameters included in the pharmacokinetic models increases the possible correlations among the parameters, this issue should be considered especially for medications in which the pharmacokinetic pro-file is a 2 or higher dimensional compartment model. MTX pharmacokinetics were previously shown to be accounted for by a 2-compartment model, [9][10][11][12][13][14][15][16][17][18][19] which suggests that this issue needs to be considered. However, to the best of our knowledge, correlations and/or covariance among population parameters have not been considered especially in the clinical use of Bayesian estimation performed using the Bayesian least-squares method.…”

Creatinine clearance rate and serum creatinine concentration are related to delayed methotrexate elimination in children with lymphoblastic malignancies

“…A number of population-based pharmacokinetic models of HDMTX infusion in patients with lymphoblastic malignancies have been described [10][11][12]. However, the clinical application of these models, particularly for patients with delayed elimination of MTX, is limited because of the considerable variation between patients in terms of MTX dosage, hydration and alkalization, renal function, coadministration of other anticancer agents, and pharmacogenomics [2,7,13].…”