Abstract Background/Aims Splitting oral methotrexate (MTX) into two doses, morning and evening (same day) is a promising strategy to improve bioavailability. It has been shown than serum levels were higher with split-dose by 28%, however, no study has examined RBC methotrexate polyglutamate levels. Methods This study utilized data and samples from an open-label RCT, SMART study, a multicentric study from India comparing single vs split-dose methotrexate (MTX) in rheumatoid arthritis (RA). It included patients of seropositive RA with duration 5 years, not on MTX or other DMARDs. Patients were treated with either single or split dose MTX for 24 weeks; started at a dose of 15 mg per week (for 2 weeks), then 20 mg per week (for 2 weeks), followed by 25 mg per week for remaining 20 weeks. In split-dose group patients took oral MTX 15 mg in morning and MTX 10 mg in evening once a week, whereas in single-dose group patients took oral MTX 25 mg once a week. For chromatographic separation of MTX polyglutamates (MTX-Glu) from RBC lysate, we used reverse-phase high-performance liquid chromatography (HPLC). Results This study includes a total of 135 patients, 67 were on split-dose and 68 on single-dose oral MTX. In 117 patients MTX-Glu levels were determined at both 16 and 24 weeks; there was a significant rise in both short-chain MTXGlu1-2 (46, 58, p 0.001) and long-chain MTXGlu3-4 levels (69,79, p = 0.004) by around 10 nMol/L. Among individual MTXGlu, Glu3 was highest (38-40%), followed by Glu1 (25-27%). On comparing the two groups, there was significantly higher level of short-chain MTXGlu1-2 with split-dose compared to single dose at both 16 and 24 weeks. However, there was no significant difference in the levels of long-chain MTXGlu3-4or total MTXglu1-4 levels. The percentage of short-chain MTXGlu1-2 (of total) was higher in split-dose. Among individual MTXGlu, MTXglu1 was significantly higher at 16 weeks, but MTXglu4 was significantly lower at 24 weeks with split-dose compared to single-dose. Conclusion This is the first study to compare RBC methotrexate polyglutamate levels (MTXGlun) between split-dose and single-dose oral methotrexate (MTX), and found higher levels of short-chain polyglutamates with split-dose MTX. Disclosure V. Dhir: None. B. Leishangthem: None. C. Prasad: None. A. Khullar: None. A. Aggarwal: None. S. Jain: None.
Dhir et al. (Wed,) studied this question.