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Population pharmacokinetic and dose optimization of mycophenolic acid in children with anti-neutrophilic cytoplasmic antibody-associated nephritis

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

Abstract

Purpose

Anti-neutrophilic cytoplasmic antibody (ANCA)–associated vasculitis is a rare autoimmune disease. Mycophenolic acid (MPA) is widely used for ANCA-associated nephritis (AAN) but with large pharmacokinetic variability. This study aims to investigate clinical factors impacting MPA disposition in pediatric AAN.

Methods

We retrospectively collected 391 MPA concentrations from 25 children diagnosed with AAN. A population pharmacokinetic model was developed to explore the potential effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimen.

Results

MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL/F, Vc/F, Vp/F, and Q/F were 0.45 h−1, 9.86 L/h, 19.69 L, 408.32 L, and 23.01 L/h. Dosage form significantly affected drug absorption. CL/F significantly decreased with increasing cystatin C, while decreasing with myeloperoxidase. Cystatin C was superior to serum creatinine in predicting apparent clearance of MPA. A dose regimen of 650 mg/m2 twice daily was required to achieve target exposure in children with normal renal function and no inflammation. The combined effects of myeloperoxidase concentration and renal function resulted in a sixfold range of MPA dose.

Conclusion

This was the first study of MPA population pharmacokinetic model in children with AAN. Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN.

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Availability of data and material

The data used to support the findings of this study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Mr. Yong-chao Fu (Tri-I Biotech Ltd., Shanghai, China) and Mr. Wu Liang (Changsha VALS Technology Co.Ltd., Hunan, China) for their guidance in model building.

Funding

This work was supported by the National Natural Science Foundation [grant number 81874325]; Scientific Research Project of Science and Technology Commission of Shanghai Municipality [grant numbers 18DZ1910604, 19XD1400900, 19DZ1910703].

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Author notes

  1. Ziwei Li and Yidie Huang contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Pharmacy, Children’s Hospital of Fudan University, National Children’s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai, 201102, China

    Ziwei Li, Yidie Huang & Zhiping Li

  2. Department of Nephrology, Children’s Hospital of Fudan University, National Children’s Medical Center, No. 399 Wanyuan Road, Minhang District, 201102, Shanghai, China

    Hong Xu

Authors
  1. Ziwei Li
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  2. Yidie Huang
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  4. Zhiping Li
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Contributions

ZWL designed the study, developed the models and wrote the manuscript. YDH were involved in patient data collection and acquisition. HX and ZPL provided support for the research and reviewed the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hong Xu or Zhiping Li.

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Ethics approval and consent to participate

This study was approved by the Research Ethics Committee from Children’s Hospital of Fudan University (No. 2020–486).

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Not applicable.

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Authors declare that they have no competing interests.

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Li, Z., Huang, Y., Xu, H. et al. Population pharmacokinetic and dose optimization of mycophenolic acid in children with anti-neutrophilic cytoplasmic antibody-associated nephritis. Eur J Clin Pharmacol 78, 831–838 (2022). https://doi.org/10.1007/s00228-021-03265-z

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  • DOI: https://doi.org/10.1007/s00228-021-03265-z

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