Low‐Dose Methotrexate Pharmacokinetics and Pharmacodynamics in the Therapy of Severe Psoriasis

Abstract

Methotrexate is an established and effective systemic treatment for severe psoriasis. Approximately 30% of patients do not respond to standard methotrexate doses while 20% discontinue therapy early in the treatment due to adverse effects, most frequently headache, nausea, gastric complaints and abnormal liver function tests. The purpose of this study was to evaluate the relationships between methotrexate pharmacokinetics and its therapeutic effect/toxicity over the initial 13 weeks of therapy. Forty-one psoriasis patients (table 1) were randomly assigned to methotrexate doses of either 7.5 mg or 15 mg administered once a week either as a bolus or with the weekly dose divided into three aliquots given at 12 hr intervals. The pharmacokinetics of methotrexate were evaluated at baseline and at week 13 and red cell concentrations of methotrexate (ERYMTX) were measured at baseline and at weeks 5, 9 and 13. The grade of skin impairment was evaluated at at weeks 1, 5, 9 and 13 using the PASI-scoring system (The Psoriasis Activity and Severity Index). The score gives an overall index for the clinical degree of psoriasis within the range of 0–72 (Finlay et al. 1990). Plasma concentrations of methotrexate were determined by HPLC (Salamoun & Frantisek 1986). The inhibition activity of erythrocyte methotrexate-polyglutamates was assayed enzymatically with dihydrofolate reductase (Schroder & Heinsvig 1985). The results of the pharmacokinetic and pharmacodynamic analyses are summarized in table 1. There was no difference between weeks 1 and 13 in the pharmacokinetic parameters of plasma methotrexate (P>0.8). Moreover, the intra-individual variability in methotrexate pharmacokinetics was 4 times less than the inter-individual variability (F-test; P<0.01).There was a strong correlation between AUCMTX at week 1 and ERYMTX concentrations at the steady state (rho=0.80, P<0.0001). Pharmacokinetic/pharmacodynamic analysis revealed a highly significant inverse relationships between PASI at week 13 (in % of the initial value) and both AUCMTX at week 1 (rho=−0.80, P<0.0001, fig. 1) and ERYMTX at the steady state (rho=−0.89, P<0.0001). Nine patients with complaints about headache and nausea on the days of methotrexate administration had the maximum plasma methotrexate concentrations (Cmax) of 0.76±0.28 μmol · l−1 as compared to 0.24±0.15 μmol · l−1 in those without this adverse effect (P=0.06). At week 13, eight patients had elevated alanine aminotransferase activities by more than 100% above the baseline. In those patients, AUCMTX at week 1 (4.2±2.4 μmol · hr · l−1) and steady-state ERYMTX (0.104±0.034 μmol · l−1) were higher than in patients with normal liver function tests (1.8±0.09 μmol · hr · l−1, P<0.02, and 0.069±0.020 μmol · l−1, P<0.05). The relationship between AUCMTX at week 1 and PASI at week 13 (in% of the initial value). In conclusion, a strong correlation was observed between methotrexate pharmacokinetics (AUCMTX) and its antipsoriatic effect (PASI). The results of this study suggest that AUCMTX within the range of 2.5–4.0 μmol · hr · l−1 and the divided-dose schedule are associated with a high successrate and a low risk of acute adverse effects of antipsoriatic therapy with methotrexate. This study was supported by the Czech Ministry of Education (Contract No. OC B15.10). The technical assistance of Ivana Tothova is gratefully acknowledged.