Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of psoriasis
Article first published online: 4 SEP 2002
British Journal of Clinical Pharmacology
Volume 54, Issue 2, pages 147–156, August 2002
How to Cite
Chládek, J., Grim, J., Martínková, J., Šimková, M., Vanı`èková, J., Koudelková, V. and Noièková, M. (2002), Pharmacokinetics and pharmacodynamics of low-dose methotrexate in the treatment of psoriasis. British Journal of Clinical Pharmacology, 54: 147–156. doi: 10.1046/j.1365-2125.2002.01621.x
- Issue published online: 4 SEP 2002
- Article first published online: 4 SEP 2002
- Received 15 August 2001,accepted 28 April 2002.
- PASI score;
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 (AUCMTX) 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 AUCMTX showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUCMTX 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 (r2=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 AUCMTX (rs=−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 (AUCMTX 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 AUCMTX values of 700 nmol l−1h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.