title: Bioequivalence study between two formulations of ciclosporin A (Cyclavance® oral solution and Atopica® soft capsules) following a single oral administration to dogs.
abstract: BACKGROUND
  Ciclosporin is a selective immunomodulator used for the treatment of atopic dermatitis in dogs. A new 100 mg/ml oral solution formulation (Cyclavance®, Virbac) was developed as a pharmaceutical equivalent to the marketed capsule formulations (Atopica®, Novartis Animal Health) containing 25, 50 mg, or 100 mg of ciclosporin A. The aim of this study was to assess and compare the pharmacokinetic profiles and bioequivalence of the two formulations following a single oral administration to dogs. This randomised, two-period, two-sequence, crossover bioequivalence study was conducted in 40 healthy dogs under fasting conditions. Each dog received either one 50 mg capsule of Atopica® or 0.5 ml of Cyclavance®. After dosing, blood samples were collected during a 48-h time period at 0, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h. Blood ciclosporin A concentrations were measured by using an HPLC-MS/MS method. Cmax, Tmax, t1/2, AUC0-t, AUC0-∞ and Kel were determined for the two ciclosporin formulations. Bioequivalence was to be concluded if the 90% confidence intervals were within the range of 80% to 125% for Cmax and AUC0-t. Dogs were monitored once daily throughout the study period for adverse effects.
  
  
  RESULTS
  The 90% confidence intervals for Cyclavance®/Atopica® mean ratios of the log-transformed pharmacokinetic variables Cmax and AUC0-t were within the conventional bioequivalence range of 80% to 125% (Point estimate: 101.2% and 101.4% respectively). Except for salivation reported after administration of both products, or vomiting and diarrhoea reported after Atopica® administration, both formulations were well tolerated in the 40 healthy dogs over the 48-h study period.
  
  
  CONCLUSIONS
  The two ciclosporin oral formulations demonstrated similar pharmacokinetic profiles and were found to be bioequivalent, and therefore, interchangeable.
authors.affiliation: Virbac, Medical Department, Carros, France. christelle.navarro@virbac.com.
authors.forename: C
authors.initials: C
authors.lastname: Navarro
authors.affiliation: , Revest les Roches, France.
authors.forename: L
authors.initials: L
authors.lastname: Séguy
authors.affiliation: AmatsiAvogadro, Bioservices department, Fontenilles, France.
authors.forename: M
authors.initials: M
authors.lastname: Vila
authors.affiliation: AmatsiAvogadro, Bioservices department, Fontenilles, France.
authors.forename: P
authors.initials: P
authors.lastname: Birckel
mesh_terms: D000818:Animals; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000662:veterinary*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004339:Drug Compounding / Q000592:standards / Q000662:veterinary*; D008297:Male; D011897:Random Allocation; D013810:Therapeutic Equivalency
chemical_list: D016572:Cyclosporine
keywords: Bioequivalence; Ciclosporin; Cyclosporine A; Dog; HPLC; Interchangeability; Pharmacokinetics; Substitution