EFFECTS OF MODERATE RENAL-INSUFFICIENCY ON PHARMACOKINETICS OF METHOTREXATE IN RHEUMATOID-ARTHRITIS PATIENTS

Objectives-To determine the effects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) pa tients. Methods-77 RA patients were included in this study MTX was adm inistered intramuscularly (7.5 to 15 mg). Subjects were divided into f our groups, according to their creatinine clearance (CLCR); group 1: C LCR lower than 45 ml/min; group 2: CLCR between 45 and 60 ml/min, grou p 3: CLCR between 61 and 80 ml/min and group 4: CLCR higher than 80 ml /min. Blood samples were collected from each subject before drug admin istration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach. R esults-MTX concentrations (total and free) were 1.3 to 1.6-times highe r in group 1 than in groups 2, 3, and 4. For total and free MTX, t(1/2 ) eliminations were 22.7 hours in group 1, 13.5 hours in group 2, 12 h ours in group 3, and 11 hours in group 4. Clearance of total MTX was 6 4, 92, 96, 115 ml/min in groups 1 to 3, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volu me of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 3 , 1.61 l/kg in group 3, and 1.56 l/kg in group 1. Elimination half lif e was significantly increased and total clearance was significantly re duced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clear ance. Conclusion-Individual testing is required rather than a general decrease of the MTX dose based only on CLCR.