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

Autor: Tan JM; University of South Australia (UniSA: Clinical and Health Sciences, Centre for Pharmaceutical Innovation), Adelaide, South Australia, Australia., Upton RN; Australian Centre for Pharmacometrics, University of South Australia, Adelaide, South Australia, Australia., Foster DJR; Clinical and Health Sciences, Australian Centre for Precision Health, University of South Australia, Adelaide, South Australia, Australia., Proudman SM; Royal Adelaide Hospital, Adelaide (South Australia), Australia. Discipline of Medicine, University of Adelaide, Adelaide, Australia., Dhir V; Clinical Immunology and Rheumatology Unit, Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India., Wiese MD; University of South Australia (UniSA: Clinical and Health Sciences, Centre for Pharmaceutical Innovation), Adelaide, South Australia, Australia.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2024 Nov; Vol. 90 (11), pp. 2763-2780. Date of Electronic Publication: 2024 Jul 05.
DOI: 10.1111/bcp.16158
Abstrakt: Aims: To 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-PG n 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.
Methods: An 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).
Results: Every 40 nmol/L increase in ery-MTX-PG 3-5 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%).
Conclusions: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.
(© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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