BIOAVAILABILITY OF HIGH DOSE METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS: A PHARMACOKINETIC ANALYSIS

Background: Although a clear relation between the pharmacokinetics of methotrexate (MTX) and its efficacy is difficult to establish, a relation between dose and efficacy was proven. For doses up to 15-20 mg week there is an increasing area under the serum concentration curve (AUC), and the bioavailability of oral and parenteral MTX is comparable in this dose range. In an attempt to improve efficacy, higher doses are being used, and the question is whether the oral route of administation allows for sufficient absorption of MTX, or that a change towards parenteral administration should be made.Objectives: To determine the bioavailabilty of higher dose (>22.5 mg) methotrexate, comparing oral and subcutaneous administration, in adult patients with rheumatoid arthritis.Methods: A pharmacokinetic analysis was performed in 15 RA patients, on a stable higher dose (>22.5 mg/week) MTX. On two occasions, two weeks apart, serum sampling was performed, once with the maintenance dose MTX orally administered, and once subcutaneously. The concurrent medication was continued. All patients had folic acid supplementation in varying doses, but not on the day of MTX intake. Blood was drawn at t=0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 8, 12, 24 and 48 hours. The MTX serumconcentrations were measured by a fluorescence polarisation immunoassay technique. An iterative two-stage Bayesian, population procedure was performed, achieving pharmacokinetic parameters for the population and for the individual patient.Results: The mean age of the patients was 60 (sd 11) years, the median disease duration 7 (range 2 to 32) years, the median BMI 26.7(range 23.7 to 40.4), the mean creatinine clearance 110 (sd 42) ml/min. The median MTX dose was 30 (range 25-40 mg) mg/week.The MTX serum concentration versus time curves were best described by a two-compartment model. The mean AUC was 2470 (sd 789) h.μg.l for oral administration, and 3822 (sd 895) h.μ.l for subcutaneous adminstration. This was significantly different (p<0.001). The mean relative bioavailability of oral MTX compared to subcutaneous, was 67%, with a range of 22 to 100%. The other pharmacokinetic parameters for the oral and subcutaneous route of administration were as follows (mean/sd): Cmax 567(204) microg/l and 532(148) microg/l, Tmax 1.3(0.4) h and 1.8(0.3) h. The volume of distribution was 11.3(2.2) l, the total body MTX clearance 8.4(3.0) l/h and the elimination half-life was 3.3(0.6) h.Conclusion: The bioavailability of oral MTX >22.5 mg/week, in adult RA patients, is highly variable, with a mean of 67%. To improve the bioavailability of MTX, a change to parenteral administration should be considered at doses >22.5 mg/week, to improve efficacy.Citation: , volume , supplement , year 2003, page Session: Rheumatoid arthritis – Treatment