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Population pharmacokinetics of mizoribine in pediatric patients with kidney disease

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Abstract

Background

The present study aimed to obtain information enabling optimisation of the clinical effect of mizoribine (MZR) in pediatric patients with kidney disease.

Methods

A total of 105 pediatric patients with kidney disease treated at our institutions were enrolled. Kidney transplant patients were excluded. Population pharmacokinetic analysis of MZR was performed based on serum concentration data. Area under the curve from time zero to infinity (AUC∞) and maximal concentration (C max) were calculated by Bayesian analysis.

Results

In children, the appearance of MZR in the blood tended to be slower and the subsequent rise in blood concentration tended to be more sluggish, compared to healthy adults. Apparent volume of distribution and oral clearance were also higher in children compared to adults. A significant positive correlation was observed between patient age and AUC∞. There were significant differences of AUC∞ and C max by age group. No relationship was observed between the administration method of MZR and serum concentration.

Conclusion

The pharmacokinetics of MZR was different in children compared to adults. To obtain the expected clinical efficacy, the regular MZR dosage schedule (2–3 mg/kg/day) might be insufficient for pediatric patients. In particular, younger patients might require a higher dosage of MZR per unit body weight.

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References

  1. Yokota S. Mizoribine: mode of action and effects in clinical use. Pediatr Int. 2002;44:196–8.

    Article  CAS  PubMed  Google Scholar 

  2. Kawasaki Y. Mizoribine: a new approach in the treatment of renal disease. Clin Dev Immunol. 2009;2009:681482.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sonda K, Takahashi K, Tanabe K, Funchinoue S, Hayasaka Y, Kawaguchi H, et al. Clinical pharmacokinetic study of mizoribine in renal transplantation patients. Transplant Proc. 1996;28:3643–8.

    CAS  PubMed  Google Scholar 

  4. Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, et al. A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int. 2000;58:317–24.

    Article  CAS  PubMed  Google Scholar 

  5. Honda M. Nephrotic syndrome and mizoribine in children. Pediatr Int. 2002;44:210–6.

    Article  PubMed  Google Scholar 

  6. Kawasaki Y, Hosoya M, Suzuki J, Onishi N, Takahashi A, Isome M, et al. Efficacy of multidrug therapy combined with mizoribine in children with diffuse IgA nephropathy in comparison with multidrug therapy without mizoribine and with methylprednisolone pulse therapy. Am J Nephrol. 2004;24:576–81.

    Article  CAS  PubMed  Google Scholar 

  7. Yoshikawa N, Nakanishi K, Ishikura K, Hataya H, Iijima K, Honda M. Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study. Pediatr Nephrol. 2008;23:757–63.

    Article  PubMed  Google Scholar 

  8. Tanaka H, Tsugawa K, Tsuruga K, Suzuki K, Nakahata T, Ito E, et al. Mizoribine for the treatment of lupus nephritis in children and adolescents. Clin Nephrol. 2004;62:412–7.

    Article  CAS  PubMed  Google Scholar 

  9. Yumura W, Suganuma S, Uchida K, Moriyama T, Otsubo S, Takei T, et al. Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis. Clin Nephrol. 2005;64:28–34.

    Article  CAS  PubMed  Google Scholar 

  10. Tanaka H, Suzuki K, Nakahata T, Tsugawa K, Ito E, Waga S. Mizoribine oral pulse therapy for patients with disease flare of lupus nephritis. Clin Nephrol. 2003;60:390–4.

    Article  CAS  PubMed  Google Scholar 

  11. Tanaka H, Tsugawa K, Suzuki K, Nakahata T, Ito E. Long-term mizoribine intermittent pulse therapy for young patients with flare of lupus nephritis. Pediatr Nephrol. 2006;21:962–6.

    Article  PubMed  Google Scholar 

  12. Kuroda T, Hirose S, Tanabe N, Sato H, Nakatsue T, Ajiro J, et al. Mizoribine therapy for patients with lupus nephritis: the association between peak mizoribine concentration and clinical efficacy. Mod Rheumatol. 2007;17:206–12.

    Article  CAS  PubMed  Google Scholar 

  13. Tanaka H, Oki E, Tsuruga K, Sato N, Matsukura H, Matsunaga A, et al. Mizoribine treatment of young patients with severe lupus nephritis: a clinicopathologic study by the Tohoku pediatric study group. Nephron Clin. Pract. 2008;110:c73–9.

    Article  CAS  PubMed  Google Scholar 

  14. Ohtomo Y, Fujinaga S, Takada M, Murakami H, Akashi S, Shimizu T, et al. High-dose mizoribine therapy for childhood onset frequently relapsing steroid-dependent nephrotic syndrome with cyclosporin nephrotoxicity. Pediatr Nephrol. 2005;20:1744–9.

    Article  PubMed  Google Scholar 

  15. Kawasaki Y, Takano K, Isome M, Suzuki J, Suyama K, Kanno H, et al. Efficacy of single dose of oral mizoribine pulse therapy two times per week for frequently relapsing nephrotic syndrome. J Nephrol. 2007;20:52–6.

    CAS  PubMed  Google Scholar 

  16. Mahmood I, Miller R. Comparison of Bayesian approach and a limited sampling model for the estimation of AUC and Cmax: a computer simulation analysis. Int J Clin Pharmacol Ther. 1999;37:439–45.

    CAS  PubMed  Google Scholar 

  17. Honda M, Itoh H, Suzuki T, Hashimoto Y. Population pharmacokinetics of higher-dose mizoribine in healthy male volunteers. Biol Pharm Bull. 2006;29:2460–4.

    Article  CAS  PubMed  Google Scholar 

  18. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20:629–37.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hosotsubo H, Takahara S, Tanaka N. Simplified high-performance liquid chromatographic method for determination of mizoribine in human serum. J Chromatogr. 1988;432:340–5.

    Article  CAS  PubMed  Google Scholar 

  20. Beal S, Boeckmann A, Sheiner L. NONMEM users guides: NONMEM Project Group. San Francisco: University of California; 1992.

    Google Scholar 

  21. Stypinski D, Obaidi M, Combs M, Weber M, Stewart AJ, Ishikawa H. Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers. Br J Clin Pharmacol. 2007;63:459–68.

    Article  CAS  PubMed  Google Scholar 

  22. Okada M, Suzuki K, Nakashima M, Nakanishi T, Fujioka N. The nucleotide derivatives inosine and inosinic acid inhibit intestinal absorption of mizoribine in rats. Eur J Pharmacol. 2006;531:140–4.

    Article  CAS  PubMed  Google Scholar 

  23. Ishida K, Takaai M, Yotsutani A, Taguchi M, Hashimoto Y. Membrane transport mechanisms of mizoribine in the rat intestine and human epithelial LS180 cells. Biol Pharm Bull. 2009;32:741–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Asahi Kasei Pharma, Tokyo, for measuring serum MZR concentrations.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Toyama City Hospital, 2-1 Imaizui-Hokubu-machi, Toyama, 939-8511, Japan

    Hisashi Kaneda

  2. Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan

    Masaki Shimizu

  3. Department of Pediatrics, Kanazawa Medical Center, 1-1 Shimoishibiki-cho, Kanazawa, 920-8650, Japan

    Kazuhide Ohta

  4. Department of Pediatrics, Yokkaichi Municipal Hospital, 2-2-37 Shibata, Yokkaichi, 510-8567, Japan

    Katsumi Ushijima

  5. Kidney Center Pediatrics, Nagoya Daini Red Cross Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, 466-8650, Japan

    Yoshimitsu Gotoh & Takuji Yamada

  6. Department of Pediatric Nephrology and Metabolism, Osaka Medical Center and Research Institute for Maternal and Child Health, 840 Murodo-cho, Izumi, 594-1101, Japan

    Kenichi Satomura

  7. Department of Pediatric Nephrology, Aichi Children’s Health and Medical Center, 1-2 Osakada, Morioka-cho, Obu, 474-8710, Japan

    Takuhito Nagai & Osamu Uemura

  8. Department of Pediatrics, Kochi Medical School, Kochi University, Oko-cho Kohasu, Nankoku, 783-8505, Japan

    Mikiya Fujieda

  9. Department of Pediatrics, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan

    Masashi Morooka

  10. Department of Pediatric Nephrology, Shizuoka Children’s Hospital, 860 Urushiyama, Aoi-ku, Shizuoka, 420-8660, Japan

    Masayoshi Yamada & Naohiro Wada

  11. Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Mari Takaai & Yukiya Hashimoto

Authors
  1. Hisashi Kaneda
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  2. Masaki Shimizu
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  3. Kazuhide Ohta
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  4. Katsumi Ushijima
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  5. Yoshimitsu Gotoh
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  6. Kenichi Satomura
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  7. Takuhito Nagai
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  8. Mikiya Fujieda
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  9. Masashi Morooka
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  10. Takuji Yamada
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  11. Masayoshi Yamada
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  12. Naohiro Wada
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  13. Mari Takaai
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  14. Yukiya Hashimoto
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  15. Osamu Uemura
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Corresponding author

Correspondence to Masaki Shimizu.

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The authors have no conflicts of interest to declare.

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Kaneda, H., Shimizu, M., Ohta, K. et al. Population pharmacokinetics of mizoribine in pediatric patients with kidney disease. Clin Exp Nephrol 20, 757–763 (2016). https://doi.org/10.1007/s10157-015-1209-9

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  • DOI: https://doi.org/10.1007/s10157-015-1209-9

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