A limited sampling method to estimate methotrexate pharmacokinetics in patients with rheumatoid arthritis using a Bayesian approach and the population data modeling program P-PHARM

Abstract

This paper describes a methodology to calculate methotrexate (MTX) pharmacokinetic parameters after intramuscular administration using two samples and the population parameters. Total and free MTX were measured over a 36-h period in 56 rheumatoid arthritis patients; 14 patients were studied after a two-dose scheme at 15-day intervals. The Hill equation was used to relate the free MTX to the total MTX changes in plasma concentrations, and a two-compartment open model was used to fit the total MTX plasma concentrations. A non-linear mixed effect procedure was used to estimate the population parameters and to explore the interindividual variability in relation to the following covariables: age, weight, height, haemoglobin, erythrocyte sedimentation rate, platelet count, creatinine clearance, rheumatoid factor, C-reactive protein, swelling joint count, and Ritchie's articular index. Population parameters were evaluated for 40 patients using a three-step approach. The population average parameters and the interindividual variabilities expressed as coefficients of variation (CV%) were: CL, 6.94 l center dot h-1 (20.5%); V, 34.8 l (32.2%); k12, 0.0838 h-1 (47.7%); k21, 0.0769 h-1 (61.6%); ka, 4.31 h-1 (58%); Emax, 1.12 mu mol center dot l-1 (19.7%); gamma, 0.932 (12.3%); and EC50, 2.14 mu mol center dot l-1 (27.3%). Thirty additional data sets (16 new patients and 14 patients of the previous population but treated on a separate occasion) were used to evaluate the predictive performance of the population parameters. Twelve blood samples were collected from each individual in order to calculate individual parameters using standard fitting procedures. These values were compared to the ones estimated using a Bayesian approach with population parameters as a priori information together with two samples, selected from the individual observations. The results show that the bias was not statistically different from zero and the precision of these parameters was excellent.

Pharmacokinetics and efficacy of low-dose methotrexate in patients with rheumatoid arthritis

“…This is because fluctuations in the pharmacokinetics (e.g., a delay in absorption or elimination) resulting from any comedication 9 may change the outcome of the analyses. In this investigation, although the mean volume of the central compartment (V d ) was smaller than that in other reports (range 25.2-34.8 l), [6][7][8] we consider that this result was derived from the difference in the average body weight of the subjects (range 64.2-75 kg). [6][7][8] To date, no report has shown a definite correlation between the efficacy and the pharmacokinetics of MTX in the treatment of RA.…”

“…However, this method is less convenient and entails higher costs. Bressolle et al 7 reported a method to estimate individual pharmacokinetic variables for MTX using a Bayesian method with two plasma concentration measurements, taken 2 h and 8 h after drug administration.…”

“…To date, analyses of population pharmacokinetics, and investigations of pharmacokinetics using a Bayesian method 5 with limited sampling have been performed. [6][7][8][9] In these studies, large interindividual variability in the pharmacokinetics of low-dose MTX has been observed, 10,11 whereas Lebbe et al 12 reported only a modest intraindividual variability. Therefore, if the efficacy of low-dose MTX correlates with its pharmacokinetics, it would be useful to determine a suitable regimen for each patient by investigating the pharmacokinetics of each individual.…”

Elevated level of serum cystatin-C concentration is a useful predictor for myelosuppression induced by methotrexate for treatment of rheumatoid arthritis

“…MTX excretion depends solely on the kidney, and clearance rates have been reported to be 43% 1 h after administration, 88% 6 h after, and 100% (completely excreted) 24 h after in cases with normal renal function [20]. Significant correlation between creatinine clearance (CrCl) level and MTX clearance rate has been reported [21][22][23][24]. Delayed clearance is associated with myelotoxicity induced by chemotherapy in the high-dose MTX regimen [25].…”

Use of Methotrexate in Older Patients

“…[14] This study demonstrated that age explained a significant part (16.8%) of the interindividual variability in estimates of clearance. The age range of the patients in this study was 24 to 70 years.…”