title: Bioequivalence and tolerability assessment of a novel intravenous ciclosporin lipid emulsion compared to branded ciclosporin in Cremophor ® EL.
abstract: BACKGROUND
  Ciclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro- and cardioprotection. The intravenous formulation currently on the market, Sandimmune(®) Injection (Sandimmune(®)), uses Cremophor(®) EL as emulsifying excipient. Cremophor(®) EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock.
  
  
  OBJECTIVE
  The primary objective was to assess if CicloMulsion(®), a Cremophor(®) EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune(®), and the secondary objective was to compare the tolerability profiles of the two preparations.
  
  
  METHODS
  This was a single-centre, open-label, subject-blind, laboratory-blind, single-dose, randomized, two-treatment, two-period, two-sequence crossover study of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according to current guidelines were performed.
  
  
  RESULTS
  The geometric mean ratios for CicloMulsion(®)/Sandimmune(®) (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC(0-last) (area under the blood concentration-time curve from time zero to time of last measurable concentration) and 0.95 (0.92, 0.97) for C(max) (maximum blood concentration). For all additional variables analysed, the 90 % CIs were also within the accepted bioequivalence range of 0.80-1.25. One anaphylactoid and one anaphylactic reaction, both classified as serious adverse events, were reported after treatment with Sandimmune(®). No serious adverse events were recorded after treatment with CicloMulsion(®).
  
  
  CONCLUSIONS
  We have assessed the pharmacokinetics and tolerability of a new Cremophor(®) EL-free lipid emulsion of ciclosporin, CicloMulsion(®), compared to Sandimmune(®). The proportion of adverse events was significantly higher for the Cremophor(®) EL-based product Sandimmune(®). We conclude that CicloMulsion(®) is bioequivalent to Sandimmune(®) and exhibits fewer adverse reactions.
authors.affiliation: NeuroVive Pharmaceutical AB (publ), Medicon Village, 223 81, Lund, Sweden. johannes.ehinger@neurovive.com
authors.forename: Karl Henrik Johannes
authors.initials: KH
authors.lastname: Ehinger
authors.forename: Magnus Joakim
authors.initials: MJ
authors.lastname: Hansson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Sjövall
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D045703:Emulsifying Agents / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D005217:Fat Emulsions, Intravenous / Q000737:chemistry*; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D013019:South Africa; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D045703:Emulsifying Agents; D005079:Excipients; D005217:Fat Emulsions, Intravenous; D007166:Immunosuppressive Agents; C000515:cremophor EL; D016572:Cyclosporine; D005990:Glycerol