title: Subcutaneous administration of methotrexate with a prefilled autoinjector pen results in a higher relative bioavailability compared with oral administration of methotrexate.
abstract: OBJECTIVE
  Methotrexate (MTX) is recognised as the cornerstone of treatment for rheumatoid arthritis. For some patients, oral MTX demonstrates variable bioavailability, especially at higher doses. Such concerns may be mitigated by subcutaneous (SC) MTX administration. This study investigated the relative bioavailability, safety, and tolerability of MTX administered either by SC injection with a prefilled autoinjector pen (MTX pen) or orally.
  
  
  METHODS
  This single-centre, open-label, randomised, 2-period, 2-sequence, single-dose, crossover study enrolled healthy subjects aged 18 to 55 years into 1 of 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg), where they received a single dose of SC MTX and of the oral MTX tablets. Blood samples were collected from subjects predose and at prespecified time points postdose for pharmacokinetic analyses. Adverse events (AEs) were recorded to assess differences in safety and tolerability.
  
  
  RESULTS
  Bioavailability, as measured by maximum plasma concentrations (Cmax) and area under the plasma-concentration curves (AUC0-t), was generally higher with the SC MTX pen compared with oral administration for all dose groups. AUC0-t ratios increased with ascending doses; Cmax ratios did not increase. A total of 80 AEs were reported in 35/62 subjects; none were severe. Differences in the safety profiles were related to the route of administration. Single administrations with the MTX pen were well tolerated at the injection site.
  
  
  CONCLUSIONS
  Single-dose administration with the SC MTX pen resulted in a higher relative bioavailability compared with oral administration. SC MTX pen administration was associated with fewer gastrointestinal AEs than oral MTX.
authors.affiliation: Professor for Medical Biometry, medac GmbH, Wedel, Germany. u.pichlmeier@medac.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Pichlmeier
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Heuer
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005260:Female; D005858:Germany; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009339:Needles; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate