Background/Purpose: Rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX) may be initiated on combination therapy with anti-TNF agents such as adalimumab. However, it is not known whether MTX doses can be reduced when adalimumab is added. Also, little is known about the disposition of intracellular MTX polyglutamates (PG). This is important because MTX PGs are thought to account for the anti-inflammatory effect of MTX in RA.

Methods: MUSICA was a 24-wk, phase 4, prospective parallel-arm study in patients with moderately to severely active RA and an inadequate response to stable, high dose MTX (≥15 mg/wk for at least 12 wks prior to Screening). Eligible subjects were randomized 1:1 to blinded oral MTX at 20 mg/wk (“high dose”) or 7.5 mg/wk (“low dose”). All patients also began open-label adalimumab 40 mg SC every other week. Blood samples were collected prior to dosing at Baseline and every 4 wks to measure adalimumab and anti-adalimumab antibody (AAA) in serum (using validated ELISA assays) and MTX PG 1 to 5 levels in erythrocytes using a validated LC-MS method. A patient was considered AAA+ if he/she had at least one serum sample with AAA level > 20 ng/mL that was confirmed by a confirmatory assay and was collected within 30 days after an adalimumab dose.

Results: Steady-state (SS) adalimumab trough levels were attained by Week 16. At Week 24, mean adalimumab trough concentrations were 8.98 µg/mL (n=155) and 7.46 µg/mL (n=154) in the high and low MTX dose groups, respectively. Overall, 11/309 patients (3.6%) were classified as AAA+ at week 24. The percentages of subjects with at least one AAA+ sample in the high and low MTX dose groups were 1.9% and 5.2%, respectively. For both MTX dose groups, new SS total MTX PG levels appeared to be reached by week 20-24. At week 24, mean total MTX PG1-5 concentrations were 130.30 nM and 60.43 nM for the high and low MTX dose groups, respectively. MTX PG1-2 (short-chain PG) were more prevalent in those treated with low MTX dose (64% of total PG) than high MTX dose (37.5% of total PG). MTX PG4-5 (long-chain PG) were however more prevalent in those treated with high MTX dose (22% of total PG) than low MTX dose (5% of total PG). Compared to the low dose group, high dose MTX resulted in a less-than-dose-proportional increase in MTX PG1-2 (mean SS levels of PG1+2 were 47.6 nM and 38.6 nM in the high and low MTX dose, respectively), a dose-proportional increase in MTX PG3 (mean SS levels of PG3 were 54.4 nM and 18.8 nM in the high and low MTX dose, respectively), and a more-than-dose-proportional increase in MTX PG4-5 (mean SS levels of PG4+5 were 28.3 nM and 3.03 nM in the high and low MTX dose, respectively).

Conclusion: In RA patients with incomplete response to MTX, slightly higher mean  adalimumab serum levels were achieved when combined with high than low MTX dose. A new SS for total MTX PG appeared to be reached by week 20-24. Short-chain PGs were more prevalent in the low MTX dose than high MTX dose; while long-chain PGs were more prevalent in the high MTX dose than low MTX dose. High dose MTX resulted in a less-than-dose-proportional increase in MTX PG1-2, a dose-proportional increase in MTX PG3, and a more-than-dose-proportional increase in MTX PG4-5 compared to the low MTX dose.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adalimumab-in-combination-with-high-and-low-dose-methotrexate-in-rheumatoid-arthritis-patients-with-inadequate-response-to-methotrexate-pharmacokinetic-results-from-the-musica-study/