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

AimsTo 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.