Pharmaceutical Research

, Volume 27, Issue 12, pp 2602–2613 | Cite as

Influence of Dosing Schedule on Organ Exposure to Cyclosporin in Pediatric Hematopoietic Stem Cell Transplantation: Analysis with a PBPK Model

  • Cécile Gérard
  • Nathalie Bleyzac
  • Pascal Girard
  • Gilles Freyer
  • Yves Bertrand
  • Michel Tod
Research Paper

ABSTRACT

Purpose

Cyclosporin is administered by intermittent infusions (II) or continuous infusions (CI) to prevent acute graft-versus-host disease (aGVHD). Because cyclosporin disposition is nonlinear, organ exposure may be higher after II than after CI, but saturation of receptors must be accounted for. The aim of the study was to compare both types of administration using a mechanistic model.

Methods

A physiologically based pharmacokinetic model was developed to estimate cyclosporin exposure and receptor occupancies (RO) in aGVHD target organs and kidneys and to compare these estimations in pediatric patients that received cyclosporin either by II or CI. The relevant biological parameters were based on a clinical study in 2 groups of pediatric patients that received cyclosporin either by II (n = 31) or CI (n = 30).

Results

Simulations showed that the exposure to cyclosporin in the interstitial fluid of aGVHD target organs was greater at day 1 after II than after CI. In kidneys, the opposite order was observed. AUCRO in all organs was greater after CI than after II. The therapeutic index (the ratio of AUCRO in blood to AUCRO in kidneys) was greater with CI than with II.

Conclusions

CI may be slightly more favorable than II for aGVHD prevention.

KEY WORDS

cyclosporin GVHD hematopoietic stem cell transplantation PBPK modelling 

Notes

ACKNOWLEDGEMENTS

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Cécile Gérard
    • 1
    • 2
  • Nathalie Bleyzac
    • 3
    • 4
  • Pascal Girard
    • 1
    • 2
  • Gilles Freyer
    • 1
    • 2
  • Yves Bertrand
    • 3
  • Michel Tod
    • 1
    • 2
    • 5
  1. 1.Université de LyonLyonFrance
  2. 2.Faculté de Médecine Lyon SudUniversité Lyon 1, EA3738, CTOOullinsFrance
  3. 3.Institut d’Hématologie et d’Oncologie PédiatriqueLyonFrance
  4. 4.Faculté de MédecineUniversité Lyon 1LyonFrance
  5. 5.PharmacieHôpital de la Croix-Rousse, Hospices Civils de LyonLyon cedex 04France

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