Population Pharmacokinetic Analysis of Tacrolimus in Adult Chinese Patients with Myasthenia Gravis: A Prospective Study.

Abstract

Tacrolimus isa widelyused immunosuppressive agent with narrow therapeutic window. Nowadays, tacrolimushasgainedacceptance as atherapeutic option in myasthenia gravis (MG) treament,however, little is known aboutits pharmacokineticcharacteristicsin MGpopulation. In this study, we aimed to investigate the population pharmacokinetic(PopPK) of tacrolimus in patients with MGand to develop model-informed dosing regimens. Trough concentrations of tacrolimus (267 measurements) and cytochrome P450 (CYP) genotypes were determined in 97 Chinese adults. The non-linear mixed-effects model was used for PopPK modeling. Monte Carlo simulations based on the established model were employed to design dosing regimens. The PopPK model was described using a one-compartment model with first-order absorption and elimination. The mean apparent clearance (CL/F) of tacrolimus was 17.1L/h, with a between-subject variability of 20.1%. Covariate screening of demographic characteristics, blood test results, co-medications, and CYP3A5*3 or CYP3A4*1G polymorphisms showed that the CYP3A5*3 genotype and co-administration of a Wuzhi capsule significantly affected tacrolimus CL/F. For patients with the CYP3A5*3*3 allele, the required tacrolimus dose for 75% of subjects to achieve target trough concentrations of 4.8-15ng/mL was 2mg every 12h (q12h). For patients with the CYP3A5*1*1 allele, the required dose was 2mg tacrolimus q12h with a Wuzhi capsule, and for patients with the CYP3A5*1*3 allele, the required dose was 3mg of tacrolimus q12h or 4mg q24h co-administered with a Wuzhi capsule. This model could be employed to optimize individualized therapies for patients with MG.