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Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients

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Abstract

Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80–125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician.

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Author information

Authors and Affiliations

  1. Clinical Pharmacology, Barts and The London, Queen Mary’s School of Medicine and Dentistry, London, EC1M 6BQ, UK

    Atholl Johnston

  2. Multi-Organ Transplant Program, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada

    Philip Belitsky

  3. Department of Nephrology and Medical Intensive Care, Charité Hospital, Berlin, Germany

    Ulrich Frei

  4. Department of Renal Medicine, Royal Prince Alfred Hospital, Camperdown, Australia

    John Horvath

  5. Department of Paediatric Nephrology, University of Essen, Essen, Germany

    Peter Hoyer

  6. Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, USA

    J. Harold Helderman

  7. Department of Clinical Chemistry, Georg-August University, Göttingen, Germany

    Michael Oellerich

  8. Department of Organ Transplantation, St. James’s University Hospital, Leeds, UK

    Stephen Pollard

  9. Renal Transplant Unit, Manchester Royal Infirmary, Manchester, UK

    Hany Riad

  10. Department of Medical and Surgical Sciences, University of Padua, Padova, Italy

    Paolo Rigotti

  11. Immunology Laboratory, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada

    Paul Keown

  12. Department of Abdominal and Transplantation Surgery, Hannover Medical School, Hannover, Germany

    Björn Nashan

Authors
  1. Atholl Johnston
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  2. Philip Belitsky
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  3. Ulrich Frei
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  4. John Horvath
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  5. Peter Hoyer
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  6. J. Harold Helderman
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  7. Michael Oellerich
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  8. Stephen Pollard
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  9. Hany Riad
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  10. Paolo Rigotti
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  11. Paul Keown
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  12. Björn Nashan
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Correspondence to Atholl Johnston.

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Johnston, A., Belitsky, P., Frei, U. et al. Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients. Eur J Clin Pharmacol 60, 389–395 (2004). https://doi.org/10.1007/s00228-004-0774-8

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  • DOI: https://doi.org/10.1007/s00228-004-0774-8

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