A Population Pharmacokinetic/Pharmacodynamic Model of Methotrexate and Mucositis Scores in Osteosarcoma

Abstract

Methotrexate, when used in high doses (12 g/m²) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age- and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and between-occasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V₁ = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V₂ = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score ≥ 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.

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 .…”

“…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.…”

“…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.…”

Delayed methotrexate elimination: Incidence, interaction with antacid drugs, and clinical consequences?

“…A population pharmacokinetic modelling approach would be interesting to better estimate methotrexate elimination rate, quantify its between‐subject variability, and identify potential influencing factors, such as the baseline or modified creatinine clearance or the coadministration of PPI or ranitidine. This pharmacokinetic model could have been subsequently linked to a pharmacodynamic model for the risk of acute renal injury, as it has been already proposed in the literature to link exposure to high‐dose methotrexate regimen to mucositis scores . However, in this study, concentrations being measured every 24 hours after methotrexate initiation until concentration fall below 0.15 μmol/L; there would therefore be a potential bias in the estimation of these elimination rates because concentrations at 48 and/or 72 hours could be considered as missing not at random.…”