Subcutaneous Methotrexate More Effective Than Oral Administration

VBCR - June 2014, Volume 3, No 3 - Rheumatoid Arthritis
E. K. Charles

Adult patients with rheumatoid arthritis (RA) may benefit from subcutaneous methotrexate (MTX) compared with oral administration of the drug, recent study findings suggest (Schiff MH, et al. Ann Rheum Dis. April 2014. Epub ahead of print).

“Methotrexate is the cornerstone of treatment in RA,” study author Michael Schiff, MD, MACR, Department of Rheumatology, University of Colorado, Denver, told Value-Based Care in Rheumatology. “This data will help clinical rheumatologists optimize the dose and delivery of methotrexate for best patient care.”

Previous Data Point to Limitations of Oral Administration
Bioavailability of oral administration of MTX varies in patients and decreases with increasing dosages, the study authors explained citing previously reported data. Oral MTX has also been associated with gastrointestinal adverse events, including nausea and vomiting, which limit optimal use. In addition, previous research that evaluated oral versus subcutaneous MTX indicated that limitations in systemic exposure of oral administration may affect efficacy. Clinical response was also better with subcutaneous MTX than with oral administration (Braun J. Arthritis Rheum. 2008;58:73-81).

As part of an 8-week, open-label, randomized-sequence, 3-way crossover phase 2 study, the investigators sought to evaluate the relative bioavailability of oral MTX and subcutaneous MTX using an MTX auto-injector, which was recently approved by the US Food and Drug Administration, in patients with RA. The secondary objective was to compare the different methods of MTX administration in terms of the time of peak concentration, terminal rate constant, and terminal half-life of MTX. Pharmaco­kinetic parameters and safety of subcutaneous and oral MTX were evaluated.

Challenging Common Practice
Patients received MTX 10 mg, 15 mg, 20 mg, or 25 mg weekly in a random sequence of 3 regimens: oral, abdomen subcutaneous injection, and thigh subcutaneous injection. Blood samples were collected for pharmacokinetic analysis and injection sites 24 hours after the administration of each treatment. Patients were eligible for inclusion if they were ≥18 years and received MTX for ≥3 months; concomitant medication had to be stable for ≥3 months.

Patients with serious comorbid disease, as well as patients taking additional medications, including disease-modifying antirheumatic drugs, that could interfere with pharmacokinetic outcome measures were excluded from the study.

Overall, 49 patients were randomized and received at least 1 dose of MTX; 47 patients completed the study. Pharmacokinetic assessments demonstrated a consistently greater bioavailability of subcutaneous MTX compared with oral MTX at all doses. Oral MTX plateaued at doses ≥15 mg compared with subcutaneous MTX, which increased in a dose-proportional manner. Treatments with both routes of administration were found to be generally safe and well tolerated with no new treatment-related safety signals identified, according to the study authors.

“The current study is the first to compare bioavailability across commonly prescribed doses of oral and subcutaneous MTX and raise the possibility that there is no advantage to increasing the oral MTX dose above 15 mg/week, a common clinical practice,” Dr Schiff and colleagues concluded. These data also suggest that subcutaneous administration may allow for optimization of MTX in patients with RA in accordance with the treatment guidelines, they added.

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