THU0182 Single Dose? Multiple Doses? Comparison of MTX-PG Concentration, Safety and Efficacy in Patients with Rheumadoid Arthritis Between Single- and Divided Dosage Regimens

Abstract

BackgroundMethotrexate (MTX) has been well-known anchor drug for rheumatoid arthritis (RA), however, dose regimen varies and it depends on countries. The divided dosage of MTX was frequently prescribed in Japan, however, the differences of safety and efficacy between divided and single dose regimens were not fully examined.ObjectivesWe conducted a preliminary study for RA patients to compare the safety, efficacy profile and MTX-polyglutamates (PGs) concentration between single- and divided dosage regimens.MethodsSingle-center Random Controlled Trial was designed. Thirty-one patients who had been insufficiently controlled by MTX (8 mg/week) were randomly assigned to 2 groups (single dose regimen/week: 15 patients; three-dose regimen/week: 16 patients). MTX dose of all patients was allowed to increase up to 16 mg/week. Safety and efficacy parameters (adverse events, the elevation of liver function tests (LFTs), WBC counts and DAS28 were monitored at baseline, 4, 8, 12 and 19 weeks. MTX-PGs in red blood cells were also detected by LC-MS/MS at same interval.ResultsThere were no significant differences in the average of age (66.3±9.2yr), disease duration (5.8yr), and baseline DAS28(CPR) (2.84±0.98) between two groups. There were also no differences in the improvement of DAS28(CPR) between two groups (-0.95±1.66 vs -0.75±1.09 respectively) and weekly MTX dose (11.5±1.6mg/week vs 11.4±1.4mg/week). Three adverse events were observed only in 3-dose regimen group (18.8%, increase in LTFs). The remarkable difference was observed in MTX-PGs, 3-dose regimen group showed significantly higher concentration of MTX-PG1+2 than single-dose group. On the other hand, 3-doses regimen group showed slight lower MTX-PG4+5 than single-dose regimen group, and there was no difference in MTX-PG3.ConclusionsThe efficacy did not show significant difference between two groups. Liver function may be affected by concentration of MTX-PG1+2, which elevated in divided dosage regimen group. Further investigation is required in a larger population.AcknowledgementsClinical registration: UMIN000012473Disclosure of InterestA. Ihata: None declared, K. Kobayashi: None declared, A. Osada: None declared, H. Sakuma: None declared, F. Tsuji Employee of: Santen Pharmaceutical. CO.,Ltd., T. Yoshimura Employee of: Santen Pharmaceutical. CO.,Ltd., C. Setoguchi Employee of: Santen Pharmaceutical. CO.,Ltd., M. Okamoto Employee of: Santen Pharmaceutical. CO.,Ltd., S. Nagaoka: None declared

Weekly split‐dose regimen for oral methotrexate reduced polyglutamation in red blood cells in patients with rheumatoid arthritis compared with single‐dose regimen: Results from a multicentered randomized control trial

“…The sample size for this study was calculated from the results of a preliminary study conducted under the same target patient conditions as this study, 8 In this preliminary study, liver dysfunction occurred in 3 out of 16 patients in the 3-dose group during the 19-…”

“…In this study, the incidence of liver dysfunction was selected as the primary endpoint based on the results of the preliminary study 8 . Although the significant increase in liver enzymes (transaminases) associated with the divided‐dose regimen that was detected in the preliminary study was confirmed, a statistically significant difference in the incidence was not detected between groups.…”

“…The sample size for this study was calculated from the results of a preliminary study conducted under the same target patient conditions as this study, 8 In this preliminary study, liver dysfunction occurred in 3 out of 16 patients in the 3‐dose group during the 19‐week observation period, whereas liver dysfunction did not occur in 15 patients in the single‐dose group. Based on the results of the preliminary study, the sample size required for analysis was 37 subjects/group to achieve 80% power with an alpha level of 5% to detect differences in liver dysfunction development.…”

“…However, in these reports, the dose was divided to ensure an interval of at least 2 days between administration in order to maintain intracellular MTX‐polyglutamates (PGs) concentration, and the method was different from the dosage and administration specified in the package insert (12‐hour interval). In a preliminary study, we compared the efficacy and safety of MTX at almost equivalent doses between a single‐dose regimen and a divided‐dose regimen (3 parts at 12‐hour intervals) 8 . Mean aspartate aminotransferase/ alanine aminotransferase (AST/ALT) levels were significantly higher in the divided‐dose regimen than in the single‐dose regimen.…”

“…In a preliminary study, we compared the efficacy and safety of MTX at almost equivalent doses between a single-dose regimen and a divided-dose regimen (3 parts at 12-hour intervals). 8 Mean aspartate aminotransferase/ alanine aminotransferase (AST/ALT) levels were significantly higher in the divided-dose regimen than in the single-dose regimen.…”