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Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Enteric-coated mycophenolate sodium (EC-MPS) is effective and safe in preventing rejection after transplantation and is mainly transported by ABCs and OATPs and metabolized by UGTs. The genetic polymorphisms affect the inter-individual variation in drug disposition and elimination. The aims of this study were to develop a population pharmacokinetic (PK) model and to evaluate the influence of genetic and clinical factors on the PK of mycophenolic acid (MPA) in Korean renal transplant recipients.

Methods

Population analysis of EC-MPS was performed using non-linear mixed effects modeling (NONMEM). After clinical and genetic factors were evaluated using a stepwise covariate method, we selected clinically relevant covariates considering covariate effects. The final model was validated by bootstrap and visual predictive check. At last, we performed the model-based simulations in order to explore an optimal dose to achieve target area under the curve (AUC) in hypothetical scenarios.

Results

From 166 plasma concentrations (n=34), a time-lagged two-compartment with a flip-flop model best describes the PK of MPA. The covariate analysis identified lower creatinine clearance (CLcr) and SLCO1B1 variant genotype were correlated with lower MPA clearance, on the contrary, UGT1A9 variant had decreased distribution of MPA, contributing to lower absorption. When considering to UGT1A9, SLCO1B1 genotypes, and renal function, the new recommended dose of 540 mg twice daily resulted in a higher success of achieving the target AUC0-12h in the 30-60 mg.h/L.

Conclusions

CLcr, UGT1A9 and SLCO1B1 genotypes seem to be promising parameters to predict the pharmacokinetics with flip-flop phenomenon of EC-MPS in transplant recipient having stable renal function. This model on clinical practice may help prevent overexposure and achieve a proper AUC in the Korean population.

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Acknowledgments

This work was supported by a Grant (11182MFDS660) from the Ministry of Food and Drug Safety in 2012 and the National Research Foundation of Korea grant, funded by the Korean Government Ministry of Science, ICT and Future Planning (no. NRF-2009-00081414).

Authorship

N.H. participated in research design, performance of the research, data analysis, and writing of the paper; H.Y. participated in research design, data analysis, and writing of the paper; I.K. participated in research design, data analysis, and writing of the paper; Y.O. and Y.K. participated in performance of the research and data analysis; J.O. participated in research design and writing of the paper.

Grants

This work was supported by the grant (11182MFDS660) from the Ministry of Food and Drug Safety in 2012 and the National Research Foundation of Korea grant, funded by the Korean Government Ministry of Science, ICT and Future Planning (no. NRF-2009-00081414).

Conflict of interest

All authors declared no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea

    Nayoung Han, In-Wha Kim & Jung Mi Oh

  2. College of Pharmacy, Chungnam National University, Daejun, South Korea

    Hwi-yeol Yun

  3. Department of Internal Medicine, Cheju Halla General Hospital, Cheju, South Korea

    Yoon Jung Oh

  4. Department of International Medicine, Seoul National University College of Medicine, Seoul, South Korea

    Yon Su Kim

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  1. Nayoung Han
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Correspondence to Jung Mi Oh.

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Han, N., Yun, Hy., Kim, IW. et al. Population pharmacogenetic pharmacokinetic modeling for flip-flop phenomenon of enteric-coated mycophenolate sodium in kidney transplant recipients. Eur J Clin Pharmacol 70, 1211–1219 (2014). https://doi.org/10.1007/s00228-014-1728-4

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