J. Chladek et al., PHARMACOKINETICS OF LOW-DOSES OF METHOTREXATE IN PATIENTS WITH PSORIASIS OVER THE EARLY PERIOD OF TREATMENT, European Journal of Clinical Pharmacology, 53(6), 1998, pp. 437-444
Objective: The aim of the present study was to investigate the pharmac
okinetics and pharmacodynamics of low-dose methotrexate (MTX) in the e
arly phase (3 months) after the start of antipsoriatic therapy. Method
s: Ten male and female psoriatic patients who failed to respond to pre
vious conventional therapy were treated with 15 mg oral MTX once per w
eek. The pharmacokinetics in plasma and the urinary excretion of MTX a
nd 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5
and 13 (corresponding to phases I, II and III, respectively). On the
same occasions, MTX accumulation in erythrocytes obtained before MTX a
dministration was investigated. Pharmacodynamics of MTX were evaluated
using the psoriasis area and severity index (PASI) score. Results: Th
ere were marked intersubject differences (range of coefficients of var
iation 34.9-76.3%) in the area under the curve (AUC), peak concentrati
on (C-max) and clearance (CL) of MTX. Total CL was proportional to ren
al clearance (CLR) (r(2) = 0.735, P < 0.0001) which accounted for 73 (
19)% of the former. There was a strong linear relationship (r(2) = 0.8
19, P < 0.0001) between CL of MTX and creatinine clearance. Within 48
h of drug administration, the urinary excretion of MTX was 46-99% of t
he dose, while that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, mor
e than 70% of the MTX dose was recovered. No intraindividual variation
s of MTX kinetic parameters during treatment were observed. MTX concen
trations in erythrocytes reached the steady-state concentration in the
range 40.7-170 nmol.l(-1) after 2 months of therapy. Pharmacodynamic
measurement versus pharmacokinetics revealed a significant inverse rel
ationship between PASI score and MTX AUC (r(s) = -0.912, P < 0.002) an
d between PASI score and erythrocytic MTX (r(s) = -0.988, P < 0.002).
Conclusion: The relationship between MTX pharmacokinetics (AUC or eryt
hrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likel
y that the efficacy of psoriasis therapy with MTX could be improved by
adjusting the dose according to plasma concentrations obtained after
the first MTX administration.