title: Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis.
abstract: OBJECTIVE
  To study the bioavailability of a divided higher oral dose of methotrexate (MTX), in comparison to a single dose, in adult patients with rheumatoid arthritis (RA).
  
  
  METHODS
  A pharmacokinetic analysis was performed in 10 patients with RA taking a stable dose (25-35 mg weekly) of MTX. Separated by one week, a pharmacokinetic analysis was performed in each patient after an oral single dose, and after an equal but split dose separated by 8 hours. MTX serum concentrations were measured by a fluorescence polarization immunoassay technique. Analysis was performed by calculation of the area under the curve (AUC) by the trapezoidal rule and by means of an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. For the population analysis, data from 15 patients in our previous study comparing oral and subcutaneous administration of MTX were also used.
  
  
  RESULTS
  The median MTX dose was 30 mg weekly (range 25-35 mg). The bioavailability of the split dose was 28% higher compared to the single dose (p = 0.007). In the population pharmacokinetic modeling, a 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after single-dose and split-dose MTX was 0.76 and 0.90, respectively, compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 oral administration regimens (p = 0.008).
  
  
  CONCLUSIONS
  The bioavailability of oral higher dose MTX in adult patients with RA can be improved by splitting the dose.
authors.affiliation: Department of Rheumatology, Medisch Spectrum Twente and University Twente, Enschede, The Netherlands. m.hoekstra@ziekenhuis-mst.nl
authors.forename: Monique
authors.initials: M
authors.lastname: Hoekstra
authors.forename: Cees
authors.initials: C
authors.lastname: Haagsma
authors.forename: Cees
authors.initials: C
authors.lastname: Neef
authors.forename: Johannes
authors.initials: J
authors.lastname: Proost
authors.forename: Antonius
authors.initials: A
authors.lastname: Knuif
authors.forename: Mart
authors.initials: M
authors.lastname: van de Laar
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate