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Subcutaneous Methotrexate Offers Superior Bioavailability Compared to Oral Administration in Patients With Rheumatoid Arthritis

Bioavailability of subcutaneously administered methotrexate is superior to orally administered higher dose (>/= 25 mg/week) methotrexate, according to a new study. This could lead to increased efficacy in patients with rheumatoid arthritis

"Our data suggest that doses between 25 and 40 mg MTX per week, administered orally, result in limited bioavailability," write Monique Hoekstra, MD, Department of Rheumatology, Medisch Spectrum Twente, Enschede, the Netherlands, and colleagues.

Methotrexate has a dose-effect relationship, although no definite relation between pharmacokinetic parameters and efficacy has been established. It is likely that an improvement in bioavailability will lead to better efficacy, report the investigators.

Previous pharmacokinetic studies in adult patients with rheumatoid arthritis demonstrated comparable bioavailability of oral and parenteral methotrexate (MTX) in doses up to 25 mg/week. It appeared that at doses above 25 mg/week, parenteral administration offered superior bioavailability though it is not known whether the bioavailability of intravenous (IV), intramuscular (IM) and subcutaneous (SC) methotrexate are strictly comparable.

In this study, a total of 15 patients treated for more than 3 months with oral or parenteral higher dose ¡Ý 25 mg/week) MTX were recruited. Pharmacokinetic analysis was performed twice, in random order, in each patient with an interval of 2 weeks between analysis. One analysis was performed with regular higher dose oral MTX and another with the same dose of subcutaneously administered MTX.

Comedication was allowed throughout the study: 3 patients used hydrochloroquine, 1 patient used sulfasalazine, and another aurothiomalate. Eight patients used low-dose (¡Ü 10 mg/day) prednisolone and 11 nonsteroidal anti-inflammatory drugs (NSAID). All patients received folic acid supplementation except on the day MTX was administered.

The bioavailability of higher dose oral MTX (¡Ý 25 mg/week) varied greatly ( range .21 to .96) with a mean value of 0.64. The area under the curve (AUC) of oral MTX was significantly lower than AUC of subcutaneous MTX (P < .001).

"The number of patients in our study with different MTX doses was too small to draw conclusions about a dose-bioavailability relation," note the researchers. "However, there is a positive relation between the subcutaneous AUC and the dose of MTX (linear regression; R² = .33, P = .03), whereas the oral AUC does not increase with an increasing dose."

"In our opinion, additional controlled trials are needed to evaluate the effect of higher doses of MTX, which are in fact widely used in rheumatology practice," the authors conclude.

J Rheumatol 2004 Apr;31:4:645-8 "Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis"

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