Population pharmacokinetics of high-dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

Abstract

The newly developed population pharmacokinetic model should improve the quality of serum concentration monitoring of high-dose MTX to predict and control toxic events.

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

“…It is well known that renal clearance is the principal pathway of MTX elimination and that the elimination of MTX appears to be related to kidney function [14][15][16]. Indeed, Skarby et al previously reported that the increase in serum creatinine (Cr) concentration within the first 12 to 24 hours after the start of MTX infusion was a good predictor of delayed elimination of MTX in Swedish children with ALL [14].…”