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CPT Pharmacometrics Syst Pharmacol. 2023 Apr 14. doi: 10.1002/psp4.12966. Online ahead of print.

ABSTRACT

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 pharmacokinetic/pharmacodynamic (PK/PD) model of tacrolimus in MG patients, in order to explore the relationships among tacrolimus dose, exposure and its therapeutic efficacy. The genotype of CYP3A5, Osserman's classification, 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 (CL/F), and total protein (TP) influenced the apparent volume of distribution (V/F) as covariates. The quantitative MG scores were characterized by the cumulated area under curve (cAUC) of tacrolimus in an Emax function. Osserman's classification was a significant covariate on the initial score of MG patients. The simulations demonstrated that tacrolimus showed an unsatisfying effect possibly due to insufficient exposure in some MG patients. A starting dose of 2 mg/d and even higher dose for patients with CYP3A5 *1/*1 & *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 MG patients, which could provide reference for the optimization of tacrolimus dosing regimen at the individual patient level.

PMID:37060188 | DOI:10.1002/psp4.12966


Source: https://pubmed.ncbi.nlm.nih.gov/3706018 ... t6+86293ac