BACKGROUND: There is a lack of published evidence on the importance of methotrexate (MTX) dose and route of administration on both its efficacy and adverse events in children with Juvenile Idiopathic Arthritis (JIA). We aimed to document our clinical practice based on the treat-to-target approach in order to support the concept that better therapeutic effect achieved with an optimal dose of parenteral MTX is associated with clinically acceptable adverse effects comparable to those reported for oral treatment. METHODS: Study inclusion criteria were indication of new MTX therapy for active arthritis in confirmed JIA patients younger than 18 years. Eligible patients were evaluated prospectively every 3 months for 1 year using standardized instruments for treatment response (American College of Rheumatology Pediatric (ACRPedi) response, Juvenile Arthritis Disease Activity Score (JADAS) 71, Clinically Inactive Disease (CID)) and adverse events (laboratory monitoring, Methotrexate Intolerance Severity Score (MISS)). MTX responders had to achieve at least ACRPedi 70 response. MTX intolerance was defined by MISS ≥ 6. RESULTS: In 45/55 patients (81.8 %) MTX was started as subcutaneous injection. The initial median weekly dose was 14.4 mg/m(2) in parenteral and 11.7 mg/m(2) in oral administration. MTX therapy was effective in the level of ACRpedi70 and CID in 50.9 % and 30.9 % of patients at month 6 and in 70.9 % and 56.4 % after 12 months of the treatment, respectively. MTX intolerance at 6 and 12 months was noted in 25.5 % and 30.6 %, respectively. Management of intolerance included change in the dose and/or route of administration, education and councelling. Adverse events led to MTX withdrawal in 5 patients (9 %) due to toxicity (n = 3) and intolerance (n = 2). We did not find any significant predictive factors for either MTX therapeutic response or intolerance. CONCLUSION: Subcutaneous MTX weekly dose around 15 mg/m(2) is associated not only with a high response rate within the first 12 months of treatment, but also with a relatively low rate of significant adverse effects that would lead to the treatment termination. It allows early recognition of MTX non-responders and addition of biologic therapy. Sustainability of therapeutic effect and longer-term evolution of adverse events will be addressed by an ongoing extension of the study.

• Klíčová slova
• Efficacy, Intolerance, Juvenile idiopathic arthritis, Methotrexate, Quality of life, Toxicity,
• MeSH
• anemie chemicky indukované   MeSH
• antirevmatika aplikace a dávkování   škodlivé účinky   MeSH
• aplikace orální MeSH
• bolesti břicha chemicky indukované   MeSH
• dítě MeSH
• injekce subkutánní MeSH
• juvenilní artritida farmakoterapie   MeSH
• Kaplanův-Meierův odhad MeSH
• lékové postižení jater etiologie   MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   škodlivé účinky   MeSH
• nauzea chemicky indukované   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• psoriatická artritida farmakoterapie   MeSH
• vředy v ústech chemicky indukované   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvracení chemicky indukované   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antirevmatika MeSH
• methotrexát MeSH

OBJECTIVE: We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. METHODS: In a 32-week, open-label, two-way cross-over study, patients (n=20, seven men, aged 35-70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n=10) or to receive the opposite sequence of treatments (arm B, n=10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. RESULTS: In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0-157) vs. 111 (73.7-175), P=0.32; week 32: 103 (55.8-173) vs. 83.6 (27.4-129), P=0.24]. After 16 weeks, the mean+/-SEM PASI decreased from 20.1+/-2.1 to 8.8+/-1.3 in arm A, while a greater reduction from 27.2+/-2.1 to 5.1+/-1.0 occurred in arm B (P<0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho=0.59, P=0.008) or RBC folate concentration (rho=0.56, P=0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. CONCLUSION: The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.

• MeSH
• adherence pacienta MeSH
• antagonisté kyseliny listové škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• aplikace orální MeSH
• dermatologické látky škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• erytrocyty metabolismus   MeSH
• klinické křížové studie MeSH
• kyselina listová škodlivé účinky   krev   terapeutické užití   MeSH
• kyselina polyglutamová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• potravní doplňky MeSH
• psoriáza farmakoterapie   MeSH
• senioři MeSH
• vitaminy škodlivé účinky   krev   terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté kyseliny listové MeSH
• dermatologické látky MeSH
• kyselina listová MeSH
• kyselina polyglutamová MeSH
• methotrexát MeSH
• vitaminy MeSH

Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX is individually highly variable, resulting in a different systemic exposure to the drug and a variable therapeutic/toxic effect in patients. The improvements and exacerbations of disease activity in relation to the introductions and discontinuations of LDMTX therapy suggest the possible immunosuppresive and anti-inflammatory properties of the drug. Because of a strong correlation between the drug pharmacokinetics and the therapeutic outcomes (pharmacodynamics), it seems to be possible to individualise the LDMTX therapy according to the results of pharmacokinetic/pharmacodynamic analysis. In the case of psoriasis, pharmacokinetic/pharmacodynamic analysis in our local study revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC(MTX) (area under the curve of methotrexate plasma concentrations; r(8) = -0.65, p < 0.001). The considerable inter-individual variability and low intra-individual variability in MTX pharmacokinetics, supports a role for therapeutic monitoring and dose individualisation at the start of pharmacotherapy. The results of this study suggest that a steady-state AUC(MTX) value of 700 nmol x h/L and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values. The preliminary results in our follow-up study suggest the statistically higher incidence of unwanted effects depending on maximum plasma concentration of the drug. Moreover, statistically significant correlation was found between the toxic effects and exposure to the drug regarding methotrexate plasma concentrations and intracellular storage in erythrocytes. However, the data are still in the process of being completed and are not yet published.

• MeSH
• antidota terapeutické užití   MeSH
• antimetabolity škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• intestinální absorpce MeSH
• kyselina listová terapeutické užití   MeSH
• leukovorin terapeutické užití   MeSH
• lidé MeSH
• methotrexát škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antidota MeSH
• antimetabolity MeSH
• kyselina listová MeSH
• leukovorin MeSH
• methotrexát MeSH

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 (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 AUC(MTX) (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)> or =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.

• MeSH
• dermatologické látky farmakokinetika   terapeutické užití   moč   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát aplikace a dávkování   analogy a deriváty   farmakokinetika   moč   MeSH
• prospektivní studie MeSH
• psoriáza farmakoterapie   metabolismus   MeSH
• senioři MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• 7-hydroxymethotrexate MeSH Prohlížeč
• dermatologické látky MeSH
• methotrexát MeSH