Abstract
The importance of tacrolimus in the treatment of myasthenia gravis (MG) as a substitute for corticosteroid-dependent immunosuppressive therapy is increasing. Thus far, however, no population pharmacokinetic (PopPK) analysis of tacrolimus in treating MG patients has been published. This article aimed to construct a PopPK model of tacrolimus for Chinese MG patients with the goal of improving its performance in MG treatment. A total of 253 trough concentration records were obtained from 83 Chinese MG patients. The effects of demographics, lifestyle and health status, biochemical test data, disease progression and treatment-related information (including co-administered medications) as covariates on the various parameters were investigated. The covariate selection was based on biological plausibility, clinical significance, statistical significance and reduction in inter-individual variability (IIV). Bootstrap and normalized prediction distribution error (NPDE) analysis were performed to validate the final model. A one-compartment PopPK model with first-order elimination and a fixed absorption phase was constructed. The estimated apparent oral clearance (CL/F) and apparent oral volume of distribution (V/F) were 3.6 L/h and 1700 L, respectively, in the MG patients. Hematocrit and blood urea nitrogen were identified as two covariates that significantly influenced the CL/F. Immunoglobulin treatment (PRO) also had the potential to influence V/F, which was consistent with the clinical observations and the high protein-binding property of tacrolimus. Other covariates including age, weight, gender and co-administered medications had no obvious influence on CL/F or V/F. The first PopPK model of tacrolimus in MG patients was established. The identified covariates were of biological plausibility and clinical importance to help individualize the dosing schedule in MG patients.
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Acknowledgements
We thank Dr Zheng JIAO from Huashan Hospital, Shanghai, for his advice on model construction. We also thank Tong-tong JIA for collecting patient information.
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Supplementary information is available on the website of Acta Pharmacologica Sinica.
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Supplementary Figure 1
Tacrolimus concentration-time curve of the supplementary dataset. (DOC 11 kb)
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Chen, Ys., Liu, Zq., Chen, R. et al. Population pharmacokinetic analysis of tacrolimus in Chinese myasthenia gravis patients. Acta Pharmacol Sin 38, 1195–1204 (2017). https://doi.org/10.1038/aps.2016.174
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DOI: https://doi.org/10.1038/aps.2016.174
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