title: Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration.
abstract: OBJECTIVE
  To compare the relative bioavailability, safety and tolerability of oral methotrexate (MTX) and subcutaneous (SC) MTX administered via an auto-injector (MTXAI) in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  In this randomised, multicenter, open-label, three-way crossover study, patients ≥18 years with adult RA undergoing treatment with MTX for ≥3 months were assigned to receive MTX 10, 15, 20 and 25 mg weekly in a random sequence of three treatments: oral, SC into the abdomen and SC into the thigh. For 24 h after administration of each treatment, blood samples were collected for pharmacokinetic analysis and injection sites were assessed.
  
  
  RESULTS
  Forty-seven patients completed the study. Systemic exposure of oral MTX plateaued at doses ≥15 mg/week. In contrast, SC MTX demonstrated a linear increase in systemic exposure that was greater than oral MTX at each dose. No unexpected AEs were noted for either formulation.
  
  
  CONCLUSIONS
  Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ≥15 mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX.
  
  
  BACKGROUND
  NCT01618968.
authors.affiliation: Department of Rheumatology, University of Colorado, Denver, Colorado, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Schiff
authors.affiliation: Clinical Development, Antares Pharma Inc, Ewing, New Jersey, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Jaffe
authors.affiliation: Medical Department, Antares Pharma Inc, Ewing, New Jersey, USA University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Freundlich
mesh_terms: D000284:Administration, Oral; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D012646:Self Administration / Q000295:instrumentation
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate
keywords: Methotrexate; Pharmacokinetics; Rheumatoid Arthritis
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