title: Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.
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.
authors.affiliation: Clinical Pharmacology, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, EC1M 6BQ, UK. A.Johnston@qmul.ac.uk
authors.forename: Atholl
authors.initials: A
authors.lastname: Johnston
authors.forename: Philip
authors.initials: P
authors.lastname: Belitsky
authors.forename: Ulrich
authors.initials: U
authors.lastname: Frei
authors.forename: John
authors.initials: J
authors.lastname: Horvath
authors.forename: Peter
authors.initials: P
authors.lastname: Hoyer
authors.forename: J Harold
authors.initials: JH
authors.lastname: Helderman
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: Stephen
authors.initials: S
authors.lastname: Pollard
authors.forename: Hany
authors.initials: H
authors.lastname: Riad
authors.forename: Paolo
authors.initials: P
authors.lastname: Rigotti
authors.forename: Paul
authors.initials: P
authors.lastname: Keown
authors.forename: Björn
authors.initials: B
authors.lastname: Nashan
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D002986:Clinical Trials as Topic; D016572:Cyclosporine / Q000008:administration & dosage* / Q000627:therapeutic use*; D004655:Emulsions; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D016377:Organ Transplantation; D013810:Therapeutic Equivalency
chemical_list: D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine