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Pharmacokinetics and pharmacodynamics of low‐dose methotrexate in the treatment of psoriasis
Author(s) -
Chládek Jaroslav,
Grim Jiøı´,
Martínková Jiøina,
Šimková Marie,
Vanı`èková Jaroslava,
Koudelková Vı`ra,
Noièková Marie
Publication year - 2002
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2002.01621.x
Subject(s) - pharmacokinetics , psoriasis , medicine , methotrexate , pharmacodynamics , psoriasis area and severity index , pharmacology , area under the curve , renal function , gastroenterology , urology , dermatology
Aims The aim of this 13 week, randomized, parallel‐group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low‐dose intermittent oral methotrexate (LDMTX) in patients with psoriasis. Methods Twenty‐four psoriatic patients (15 male and 9 female, aged 31–73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASI‐scoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times. Results The comparison of the areas under the plasma concentration‐time curve (AUC MTX ) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two‐way anova (factors: subject and the week of therapy) on the log‐transformed AUC MTX showed no effect of the week of therapy ( P >0.8). Moreover, the intraindividual variability in the AUC MTX was at least 4‐fold less than the interindividual variability ( F ‐test; P <0.01). The steady‐state total plasma clearance of MTX ranged from 5.0 to 18.2 l h −1 and was proportional to the renal clearance ( r 2 =0.45, P <0.001) which accounted for 65±20% of the former. The renal clearance of 7‐OHMTX was approximately 4–8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady‐state AUC MTX ( r s =−0.65, P <0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P =0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)≥700 nmol l −1 h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l −1 h were responders ( P <0.01, Fisher's exact test). Conclusions A strong correlation was observed between the pharmacokinetics (AUC MTX at the steady state) and antipsoriatic effect (PASI‐score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUC MTX values of 700 nmol l −1 h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.