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

被引:0
|
作者
Tan, Jiun Ming [1 ]
Upton, Richard N. [2 ]
Foster, David J. R. [3 ]
Proudman, Susanna M. [4 ,5 ]
Dhir, Varun [6 ]
Wiese, Michael D. [1 ]
机构
[1] Univ South Australia, Ctr Pharmaceut Innovat, UniSA Clin & Hlth Sci, Adelaide, SA, Australia
[2] Univ South Australia, Australian Ctr Pharmacometr, Adelaide, SA, Australia
[3] Univ South Australia, Australian Ctr Precis Hlth, Clin & Hlth Sci, Adelaide, SA, Australia
[4] Royal Adelaide Hosp, Adelaide, SA, Australia
[5] Univ Adelaide, Discipline Med, Adelaide, Australia
[6] Post Grad Inst Med Educ & Res, Dept Internal Med, Clin Immunol & Rheumatol Unit, Chandigarh, India
关键词
methotrexate; parenteral route; population pharmacokinetic-pharmacodynamic modelling; precision dosing; rheumatoid arthritis; simulation; RED-BLOOD-CELLS; POLYGLUTAMATE CONCENTRATIONS; POPULATION PHARMACOKINETICS; ORAL METHOTREXATE; DISEASE-ACTIVITY; ROUTE; THERAPY; DOSAGE; POLYMORPHISMS; DETERMINANTS;
D O I
10.1111/bcp.16158
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:2763 / 2780
页数:18
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