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Population PK/PD model of tacrolimus for exploring the relationship between accumulated exposure and quantitative scores in myasthenia gravis patients

Tacrolimus is an important immunosuppressant used in the treatment of myasthenia gravis (MG). However, the population pharmacokinetic (PK) characteristics together with the exposure‐response of tacrolimus in the treatment of MG remain largely unknown. In this study, we aimed to develop a population...

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Detalles Bibliográficos
Autores principales: Chen, Di, Yao, Qingyu, Chen, Wenjun, Yin, Jian, Hou, Shifang, Tian, Xiaoxin, Zhao, Ming, Zhang, Hua, Yang, Liping, Zhou, Tianyan, Jin, Pengfei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349186/
https://www.ncbi.nlm.nih.gov/pubmed/37060188
http://dx.doi.org/10.1002/psp4.12966
Descripción
Sumario:Tacrolimus is an important immunosuppressant used in the treatment of myasthenia gravis (MG). However, the population pharmacokinetic (PK) characteristics together with the exposure‐response of tacrolimus in the treatment of MG remain largely unknown. In this study, we aimed to develop a population PK/pharmacodynamic (PK/PD) model of tacrolimus in patients with MG, in order to explore the relationships among tacrolimus dose, exposure, and its therapeutic efficacy. The genotype of CYP3A5, Osserman's classification, and status of thymus, as well as demographic characteristics and other biomarkers from laboratory testing were tested as covariate, and simulations were performed based on the final model. The population PK model was described using a one‐compartment model with first‐order elimination and fixed absorption parameters. CYP3A5 genotype significantly influenced the apparent clearance, and total protein (TP) influenced the apparent volume of distribution as covariates. The quantitative MG scores were characterized by the cumulated area under curve of tacrolimus in a maximum effect function. Osserman's classification was a significant covariate on the initial score of patients with MG. The simulations demonstrated that tacrolimus showed an unsatisfying effect possibly due to insufficient exposure in some patients with MG. A starting dose of 2 mg/d and even higher dose for patients with CYP3A5 *1/*1 and *1/*3 and lower TP level were required for the rapid action of tacrolimus. The population PK/PD model quantitatively described the relationships among tacrolimus dose, exposure, and therapeutic efficacy in patients with MG, which could provide reference for the optimization of tacrolimus dosing regimen at the individual patient level.