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

Abstract

This article evaluates the relationship between the pharmacokinetics of methotrexate (MTX), its efficacy in the treatment of rheumatoid arthritis (RA), and serum folic acid (FA) levels. The pharmacokinetics of MTX was studied in 29 patients with RA treated with low-dose MTX. The weekly dose of MTX was given orally at 2-4 mg every 12 h over a period of 24-36 h. Blood samples were taken 4 h after the first administration in any given week. A Bayesian method was used to estimate individual MTX pharmacokinetic variables. We then investigated the efficacy of MTX and the serum FA levels in these patients. We examined C-reactive protein levels (CRP) and the erythrocyte sedimentation rate (ESR), and analyzed the values obtained before and after MTX treatment in order to evaluate the efficacy of the MTX treatment. The degree of improvement in CRP and ESR was significantly correlated with the length of time the MTX concentration-time curve remained above 0.02 microM in one week. Furthermore, the degree of improvement in CRP was also significantly correlated with the area under the concentration-time curve (AUC) for MTX. These results suggest that serum MTX measurements could be useful in determining individual patient regimens.

Higher maximal serum concentration of methotrexate predicts the incidence of adverse reactions in Japanese rheumatoid arthritis patients

“…Notably, MTX was commonly effective for arthritis in our patients, despite a lower C max than those values reported in Western countries. [11][12][13] Hiraga et al 8 reported that the mean C max of MTX after the fi rst administration of the week was 0.241 µmol/l, and demons trated the effi cacy of MTX. The relationship between the effi ciency of MTX and C max needs to be further studied in Fig.…”

“…Shiozawa et al 7 demonstrated that the mean maximal serum MTX concentration was achieved at 1-2 h after the intake of the fi rst dose of the week, and the pharmacodynamics of the MTX of the Japanese patients was comparable with those overseas. Another group also showed the relationship between the serum MTX concentration 8 . Hiraga et alreported that the improvement of C-reactive protein (CRP) levels by MTX therapy signifi cantly correlated with the area under the concentration-time curve for MTX.…”

Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study

“…Therefore, they are unreliable for predicting the efficacy or toxicity of MTX in patients with RA 6–12. In contrast, MTX-PG concentrations in erythrocytes have been identified as a potentially promising biomarker associated with response to MTX in patients with RA and juvenile idiopathic arthritis 12–17.…”

Folate Depletion and Increased Glutamation in Juvenile Idiopathic Arthritis Patients Treated With Methotrexate

“…The majority of efforts to identify clinical biomarkers for MTX therapy have focused on measures of drug disposition. Despite a high degree of interindividual variability in plasma pharmacokinetics, plasma MTX has not been found to be consistently associated with drug response in inflammatory arthritis (), and is of limited utility as a tool for therapeutic drug monitoring in these patients. The realization that MTX is metabolized intracellularly through the addition of glutamate residues, similar to endogenous folates, forming pharmacologically active species, has resulted in efforts to correlate clinical response with MTX polyglutamate concentrations in red blood cells (RBCs) ().…”