Methotrexate Polyglutamates Exposure - Response Modeling in a Large Cohort of Rheumatoid Arthritis Patients starting Methotrexate

Clin Pharmacol Ther. 2023 Jun 14. doi: 10.1002/cpt.2974. Online ahead of print.ABSTRACTMethotrexate polyglutamates (MTX-PG) concentrations in red blood cells (RBC) have been suggested as a biomarker of response in rheumatoid arthritis (RA) patients receiving low-dose MTX therapy. We investigated the association and inter-patient variability between RBC-MTX-PG3-5 -exposure and response in RA patients starting MTX. Data of three prospective cohorts were available. The relationship between exposure and Disease Activity Score (DAS28) was analysed using a population pharmacokinetic-pharmacodynamic (PKPD) model. Relevant covariates were tested using full covariate modelling and backward elimination. From 395 patients, 3401 MTX-PG concentrations and 1337 DAS28 measurements were available between 0-300 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: 69.3nmol/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 female and 10% lower (95%CI 7.7%-12.4%) in a 65 compared to a 35-year-old patient. MTX-PG3-5 concentrations associated with DAS28: EC50 was 9.14 nmol/L (95%CI 4.2nmol/L-14.1nmol/L). EC80 above 47 nmol/L was regarded optimal response. Independent of the MTX-PG 3-5 - response association, co-administration of DMARDs and corticosteroi...
Source: Clinical Pharmacology and Therapeutics - Category: Drugs & Pharmacology Authors: Source Type: research