COMBINATION OF METHOTREXATE AND SULFASALAZINE IN PATIENTS WITH RHEUMATOID-ARTHRITIS - PHARMACOKINETIC ANALYSIS AND RELATIONSHIP TO CLINICAL-RESPONSE

1 The influence of sulphasalazine (SASP) on the pharmacokinetics of lo w dose methotrexate (MTX) and the relation between pharmacokinetic var iables and clinical response was studied in 15 patients with active rh eumatoid arthritis despite > 6 months of SASP treatment. 2 SASP was st opped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was adm inistered after a standard breakfast. Blood was sampled initially ever y 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks t he same procedure was repeated supplemented with concomitant administr ation of 1000 mg SASP. Clinical measurements included Ritchie articula r index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two-compartment model with first order absorption and lag time. Results are given as mean (s .d.). Paired t-test or signed rank test were applied in the statistica l analysis. 3 Pharmacokinetics of MTX without vs with SASP, means +/- s.d. were as follows: AUC: 673 +/- 179 vs 628 +/- 210 (95% confidence interval [CI] of the difference was -71 to 159) ng ml(-1) h, MRT: 5.2 +/- 1.3 vs 5.2 +/- 1.1 (95% CI -0.4 to 0.4) h, t(1/2,z): 4.3 +/- 1.1 v s 4.2 +/- 1.1 (95% CI -0.3 to 0.5) h, V/F: 59.3 +/- 29.3 vs 65.5 +/- 2 5.3 (95% -23.8 to 11.4) 1, CL/F: 12.3 +/- 5.0 vs 13.5 +/- 4.8 (95% CI -4.5 to 2.3) 1 h(-1). CL(R)/F: 6.2 +/- 1.3 vs 6.3 +/- 2.1 (95% CI -1.3 to 1.1) 1 h(-1). All P values were greater than or equal to 0.3. 4 A weak correlation existed between the change of ESR and the MRT, the t( 1/2,z) and the V/F (Spearman correlation coefficients of 0.43, 0.50 an d 0.50 respectively, 0.05 < P < 0.1). 5 There is no significant influe nce off chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consist ently with some pharmacokinetic variables of MTX.