Pharmacokinetic‐pharmacodynamic modelling and simulation of methotrexate dosing in patients with rheumatoid arthritis

Abstract

AbstractAimsTo develop a non‐linear mixed‐effects population pharmacokinetic and pharmacodynamic (PK‐PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery‐MTX‐PGn with “n” number of glutamate, representing PK component) and how this relates to modified 28‐joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS‐28‐3) for rheumatoid arthritis (RA), representing PD component.MethodsAn existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK‐PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate).ResultsEvery 40 nmol/L increase in ery‐MTX‐PG3‐5 total concentration correlated with 1‐unit reduction in DAS‐28‐3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS‐28‐3 when other variables were constant) and patient age (every 10‐year increase in age correlated with 3.4% increase in DAS‐28‐3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%).ConclusionsA loading dose regimen was more likely to achieve higher ery‐MTX‐PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.