Background/Purpose: Higher exposure and lower immunogenicity rates have been observed for adalimumab when co-administered with methotrexate (MTX) compared to adalimumab monotherapy. The CONCERTO study was designed to evaluate the effect of fixed MTX doses on adalimumab exposure and to assess the pharmacokinetics of MTX polyglutamates 1, 2, 3, 4 and 5 (PG1-5) in red blood cells in MTX and biologic-naïve RA patients. The efficacy and safety from the CONCERTO study was previously reported.

Methods: CONCERTO was a Phase 4, 26-wk, double-blind, and parallel-arm trial in MTX and biologic-naive patients with active RA. Subjects were randomized 1:1:1:1 to blinded weekly oral MTX doses (2.5, 5, 10, or 20 mg). MTX dose remained constant throughout the entire study for the 2.5, 5 and 10 mg per wk MTX groups. Subjects in the 20 mg MTX group started on 10 mg MTX per wk which increased every two wks by 2.5 mg until reaching 20 mg per wk at Wk 8-Wk 26. All subjects received open-label adalimumab 40 mg sc every other wk and took 5 mg weekly supplement of oral folate. Blood samples were collected at baseline and prior to dosing at Wks 2, 4, 8, 12, 16, 20 and 26 for analysis of adalimumab and anti-adalimumab antibodies (AAA) in serum and analysis of MTX PG1-5 in red blood cell (RBC). Adalimumab and AAA were determined using validated ELISA methods. MTX PG1-5 concentrations were measured using a validated LC-MS method. A patient was considered AAA+ if at least one sample had measured AAA greater than 20 ng/mL and was confirmed by the confirmatory assay within 30 days after an adalimumab dose.

Results: Adalimumab trough concentrations appeared to reach steady state by Wk 16. At Week 26, mean adalimumab concentration in the 2.5 and 5 mg per week MTX dose groups was 4.4 μg/mL (N=98) and 5.7 μg/mL (N=100), respectively. Mean adalimumab concentration at higher MTX doses (10 to 20 mg weekly) was approximately 6.5 μg/mL (N=98 for each group) at Wk 26. Forty six patients (46/394, 12%) were classified as AAA+ during the study. The percents of subjects with at least one AAA+ sample for the 2.5, 5, 10 and 20 mg MTX per week dose group were 21%, 13%, 6%, and 6% respectively. At Week 26, mean MTX PG1-5 concentrations in RBC were 19.4, 34.2, 62.8, and 119 nM for the 2.5, 5, 10 and 20 mg MTX dose groups, respectively. Time to achieve steady state PG concentration was shorter for short chain PG1-2 (4 weeks) compared to longer chain PG3-5 (20- >26 weeks), leading to longer times to reach steady state as MTX dose increased. Higher MTX doses resulted in higher percentages of longer chain PG3-5. Short-chain PG1-2 were less than dose proportional and longer chain PG3-5 were greater than dose proportional.

Conclusion: In MTX and biologic-naive patients with active RA who received a fixed dose of MTX, the mean adalimumab exposure increased with increasing MTX dose from 2.5 to 10 mg MTX; adalimumab exposure was similar following 10 or 20 mg MTX. The percent of subjects with at least one AAA positive sample decreased with increasing MTX dose up to 10 mg MTX. Time to MTX steady state is dependent on MTX dose and is longer for higher MTX doses. As MTX dose increases, the percentage of PG1-2 increases less than dose proportionally while the percentage of PG3-5 increases more than dose proportionally.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adalimumab-and-methotrexate-pharmacokinetics-following-combination-therapy-with-different-methotrexate-doses-in-methotrexate-and-biologic-naive-rheumatoid-arthritis-patients-concerto-s/