Population pharmacokinetic investigation of low-dose methotrexate in rheumatoid arthritics Japanese patients.
OBJECTIVE
To estimate the population pharmacokinetics of low-dose methotrexate (MTX) in Japanese patients using nonmem, a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data.


METHODS
A total of 153 serum concentration measurements obtained from the 17 healthy volunteers and 17 patients with rheumatoid arthritis were collected. Analysis of the pharmacokinetics of MTX was accomplished using a two-compartment pharmacokinetic model with first-order absorption. The effect of a variety of developmental and demographic factors on MTX disposition was investigated.


RESULTS
The final pharmacokinetic parameters were CL/F (L/kg/h) = 0.177 x 0.394MULT, V1/F (L/kg) = 0.0501, Q/F (L/kg/h) = 0.056, V2/F (L/kg) = 0.368, ka (h-1) = 0.503, where CL is total body clearance, V1 and V2 is apparent volume of distribution in the central and peripheral compartments, k(a) is absorption rate constant, Q is intercompartmental clearance and MULT = 1 for patients received multiple dosing and zero otherwise. The interindividual variabilities in CL, Q and V1 were 25.7%, 22.3% and 217.9%, respectively, and the residual variability was 17.8% as a coefficient of variation. Because of the lake of information on data set we were unable to characterize the interindividual variability for V2 and ka.


CONCLUSIONS
Clinical application of the model to patient care may permit selection of an appropriate dosage to achieve target MTX concentrations, thus enabling the clinician to achieve the desired therapeutic effect in Japanese patients. However, the MTX dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.
Yukawa
E
E
Laboratory of Evidence-based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Minami-Ku, Fukuoka, Japan. yukawa@daiichi-cps.ac.jp
Mori
S
S
Ueda
K
K
Nakada
Y
Y
D000328:Adult; D018501:Antirheumatic Agents / Q000493:pharmacokinetics*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D008954:Models, Biological
D018501:Antirheumatic Agents; D008727:Methotrexate