AB0251 INCREASED ACCUMULATION OF ERYTHROCYTE METHOTREXATE POLYGLUTAMATES DURING EARLY PHASE SUBCUTANEOUS VERSUS ORAL METHOTREXATE TREATMENT OF RHEUMATOID ARTHRITIS PATIENTS

Abstract

Background:Optimal dosing of methotrexate (MTX) for individual rheumatoid arthritis (RA) patients to achieve adequate disease control is an ongoing challenge. Assessment of erythrocyte MTX-polyglutamates (PGs) levels has been employed as a tool to monitor clinical response of RA patients in the first 3-12 months of treatment and MTX-PG2-4 and total MTX-PGs were associated with a lower DAS28 over 9 months.1 However, data from earlier time points, MTX-PG6 and per route of administration are unavailable.Objectives:To investigate the pharmacokinetics and -dynamics of erythrocyte MTX-PG accumulation in RA patients receiving oral or subcutaneous MTX in the early phase (1, 2, and 3 months) of MTX treatment initiation.Methods:In a clinical prospective cohort study (MeMo study (NTR7149)), newly diagnosed RA patients were administered oral (n=24) or subcutaneous (n=22) MTX, mostly according to the COBRA-light schedule (start 10 mg MTX, increased to 25 mg MTX in 8 weeks). At 1, 2, and 3 months after start of therapy, blood was collected and individual MTX-PGs (MTX-PG1 – MTX-PG6) were analyzed in erythrocytes at a minimal detection limit of 1 nmol/L, using a validated UHPLC-MS/MS method with labeled internal standards.1 Dosing, concomitant treatments and DAS28-ESR assessments were in conformity with clinical practice. Adverse events were recorded.Results:46 consecutive patients were included in this study; 76% female, mean age: 57.8 years, BMI: 25.8, 20% smokers, mean baseline DAS28-ESR: 3.5. Notwithstanding marked interpatient variability, patients starting subcutaneous MTX had accumulated significantly higher (approximately 2-fold) long chain MTX-PGs (MTX-PG4-6) when compared to patients in the oral MTX group at 1 and 2 months (Figure 1A, Table 1). Similarly, MTX-PG1-6 and MTX-PG3 accumulation were higher in subcutaneous MTX-users at month 1 (p=0.022 and p=0.011) compared to the oral group (median 68.6 nmol/L (IQR:40.5) vs 51.9 (55.6) and 17.4 (11.1) vs 11.2 (15.6), respectively (Figure 1B, Table 1).Table 1.Linear regression of MTX-PG levels and administration route, corrected for age, baseline DAS28, smoking, BMI, eGFR and MTX dose.monthß (P-value)1ß (P-value)2ß (P-value)3MTX-PG1-61.65 (0.022)1.51 (0.073)1.30 (0.233)MTX-PG1,21.13 (0.599)1.19 (0.470)1.12 (0.623)MTX-PG31.75 (0.011)1.51 (0.071)1.19 (0.439)MTX-PG4-61.97 (0.036)2.04 (0.033)1.55 (0.136)Mean MTX dose at baseline was 10.5mg (SD 1.5) for both groups, 15.4 (4.4) and 16.8 (1.8) at 1 month and 22.8 (3.9) and 22.4 (5.2) at 2 months for oral and subcutaneous use respectively.DAS28 decreased with 1.6 in the oral group and 1.1 in the subcutaneous group (p=0.382). With and without corrections for age, baseline DAS28, eGFR, MTX dose (1 month before sampling), smoking and BMI, no significant relation between MTX-PG concentrations and DAS28 was observed during the first 3 months of treatment.43 patients reported any side effect, mostly headache and dizziness, which was similar in both groups and uncorrelated with MTX-PG levels.No association was found between MTX-PG1 levels and number of days between timing of blood withdrawal and last administration.Figure 1.Erythrocyte long chain MTX-PG(A) and total MTX-PG(B) accumulation in RA patients of the first 3 months of oral(C) or subcutaneous(D) MTX administration. At 3 months, 18 patients using oral and 18 patients using subcutaneous MTX were still continuing MTX treatment. Medians and IQR are depicted.Conclusion:This study shows the feasibility of measuring erythrocyte MTX-PGs early on in the treatment of RA patients with MTX and demonstrated significantly higher accumulation of MTX-PGs following subcutaneous versus oral MTX administration. Early phase erythrocyte MTX-PG analyses may hold potential for positioning in optimizing individual patient MTX dose scheduling.