Methotrexate Polyglutamates Exposure – Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients Starting Methotrexate

Abstract

Methotrexate polyglutamates (MTX‐PG) concentrations in red blood cells (RBCs) have been suggested as a biomarker of response in patients with rheumatoid arthritis (RA) receiving low‐dose MTX therapy. We investigated the association and interpatient variability between RBC‐MTX‐PG3‐5‐exposure and response in patients with RA starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score in 28 joints (DAS28) was analyzed using a population pharmacokinetic‐pharmacodynamic model. Relevant covariates were tested using full covariate modeling and backward elimination. From 395 patients, 3,401 MTX‐PG concentrations and 1,337 DAS28 measurements were available between 0 and 300 days after MTX treatment onset. The developed model adequately described the time course of MTX‐PG3‐5 and DAS28. The median MTX‐PG3‐5 level at month 1 was 30.9 nmol/L (interquartile range (IQR): 23.6–43.7; n = 41) and at month 3: 69.3 nmol/L (IQR: 17.9–41.2; n = 351). Clearance of MTX‐PG3‐5 from RBCs was 28% lower (95% confidence interval (CI): 23.6–32.8%) in a woman and 10% lower (95% CI: 7.7–12.4%) in a 65‐year‐old compared with a 35‐year‐old patient. MTX‐PG3‐5 concentrations associated with DAS28: half‐maximal effective concentration (EC50) was 9.14 nmol/L (95% CI: 4.2 nmol/L‐14.1 nmol/L). EF at 80% (EC80) above 47 nmol/L was regarded as the optimal response. Independent of the MTX‐PG 3–5 – response association, co‐administration of disease‐modifying antirheumatic drugs and corticosteroids improved response (additive effect on maximum effect (Emax)), whereas smoking, high body mass index and low albumin decreased Emax. In patients with RA starting MTX, RBC‐MTX‐PG3‐5 was associated with clinical response. A dose increase is suggested when MTX‐PG3‐5 at month 1 is below 9.15 nmol/L, continued with the same dose when the concentration is above 47 nmol/L, and consider other treatment options above 78 nmol/L from 3 months onwards.

Editorial: Monitoring methotrexate polyglutamates in Crohn's disease—Authors' reply

“…>50 nmol/L for MTX‐PG 3 at 3 months treatment) matched those previously observed in other IMIDs 3 (>60 nmol/L MTX‐PG 3 5 , >74 nmol/L MTX‐PG total 6 , >83 nmol/L MTX‐PG total 7 . Combination of our three prospective RA cohorts in a PKPD modelling study, revealed an effective concentration range of 47–78 nmol/L MTX‐PG 345 at 3 months of therapy 4 . Thus, the PKPD prerequisites for applying TDM have been met.…”

“…Our study identified MTX‐PG 3 as the most suitable parameter for therapeutic drug monitoring (TDM). MTX‐PG 345 emerged as a viable alternative, based on its correlation with biochemical response in our cohort and the results of a recent pharmakinetic/pharmacodynamic (PKPD) modelling study in RA 4 . The next step is to establish a therapeutic range or threshold.…”