Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients

Abstract

Objectives-To determine the eVects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) patients. Methods-77 RA patients were included in this study. MTX was administered intramuscularly (7.5 to 15 mg). Subjects were divided into four groups, according to their creatinine clearance (CL CR ); group 1: CL CR lower than 45 ml/min; group 2: CL CR between 45 and 60 ml/min, group 3: CL CR between 61 and 80 ml/min and group 4: CL CR higher than 80 ml/min. Blood samples were collected from each subject before drug administration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach. Results-MTX concentrations (total and free) were 1.3 to 1.6-times higher 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 hours in group 3, and 11 hours in group 4. Clearance of total MTX was 64, 92, 96, 115 ml/min in groups 1 to 4, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volume of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 2, 1.61 l/kg in group 3, and 1.56 l/kg in group 4. Elimination half life was significantly increased and total clearance was significantly reduced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clearance. Conclusion-Individual testing is required rather than a general decrease of the MTX dose based only on CL CR .

Determinants of red blood cell methotrexate polyglutamate concentrations in rheumatoid arthritis patients receiving long‐term methotrexate treatment

“…Studies of serum MTX concentrations have demonstrated decreased clearance and increased elimination half-life of MTX with renal impairment (12). From data pooled from 11 clinical trials including 496 patients, an increase in adverse effects of MTX in patients with renal impairment was reported, with an ϳ4-fold increase in the odds of severe toxicity in these patients.…”

“…Twenty (10.4%) were receiving another DMARD (4 sulfasalazine, 9 hydroxychloroquine, 5 sulfasalazine and hydroxychloroquine, 1 leflunomide, and 1 leflunomide and hydroxychloroquine). Fifty-nine patients (30.7%) were receiving oral prednisone, at a mean daily dosage of 5.8 mg (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20].…”

Two Drug Interaction Studies Evaluating the Pharmacokinetics and Toxicity of Pemetrexed When Coadministered with Aspirin or Ibuprofen in Patients with Advanced Cancer

“…The primary route of elimination for both pemetrexed and methotrexate is renal excretion of unchanged drug in the urine (8,12). Like methotrexate, the clearance of pemetrexed is decreased in patients with renal insufficiency (13,14). For both drugs, decreased clearance results in greater systemic exposure, which may be associated with increased toxicity.…”

Pemetrexed Safety and Pharmacokinetics in Patients with Third-Space Fluid

“…The primary route of elimination for both pemetrexed and methotrexate is renal excretion of unchanged drug in the urine (13,14). Like methotrexate, the clearance of pemetrexed is decreased in patients with renal insufficiency (15,16). For both drugs, decreased clearance results in greater systemic exposure, which may be associated with increased toxicity.…”