title: The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Charles University, Simkova 870, 500 38, Hradec Kralove, Czech Republic. chladekj@lfhk.cuni.cz
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Chládek
authors.forename: Marie
authors.initials: M
authors.lastname: Simková
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Vanecková
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.forename: Jirina
authors.initials: J
authors.lastname: Chládkova
authors.forename: Jirina
authors.initials: J
authors.lastname: Martínková
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Vávrová
authors.forename: Martin
authors.initials: M
authors.lastname: Beránek
mesh_terms: D000284:Administration, Oral; D000368:Aged; D018592:Cross-Over Studies; D003879:Dermatologic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019587:Dietary Supplements; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008875:Middle Aged; D010349:Patient Compliance; D011099:Polyglutamic Acid / Q000097:blood; D011565:Psoriasis / Q000188:drug therapy*; D014815:Vitamins / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*
chemical_list: D003879:Dermatologic Agents; D005493:Folic Acid Antagonists; D014815:Vitamins; D011099:Polyglutamic Acid; D005492:Folic Acid; D008727:Methotrexate