Bioequivalence study between two formulations of ciclosporin A (Cyclavance® oral solution and Atopica® soft capsules) following a single oral administration to dogs

Abstract

BackgroundCiclosporin 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.ResultsThe 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.ConclusionsThe two ciclosporin oral formulations demonstrated similar pharmacokinetic profiles and were found to be bioequivalent, and therefore, interchangeable.

Comparison of whole blood concentrations of oral human generic modified ciclosporin capsules with microemulsified ciclosporin capsules approved for canine atopic dermatitis following a single oral administration to healthy dogs

“…The dogs used in our study were healthy, male‐castrated adult research beagle dogs. Beagle dogs are frequently used in studies evaluating blood concentrations of drugs including ciclosporin 10,12 . In the bioequivalence study demonstrating interchangeability between Cyclavance and Atopica, the 40 dogs that were used were healthy, male adult research beagle dogs 10 …”

“…This study was designed as a single dose, randomised, blinded, cross-over study with a wash-out period of eight days between treatments; the framework for this study was adapted from a bioequivalence study published previously comparing two ciclosporin formulations following a single oral administration to dogs. 10 The eight dogs were randomly assigned to groups and received a single oral dose of 50 mg of ciclosporin capsule formulation (Teva; Treatment A) or 50 mg Atopica (Treatment B); the mean dose and range of ciclosporin were 4.8 mg/kg and 4.4-5.3 mg/kg/day, respectively. After an eight-day washout period, the dogs were administered the other treatment.…”

“…The blood collection time points were chosen based on whole blood ciclosporin concentrations from previous pharmacokinetic studies of Atopica capsules administered orally to dogs as a single dose. 10,12 Dogs were monitored for any adverse effects, including salivation, diarrhoea, vomiting and decreased appetite. All dogs were fasted for ≥15 h before each treatment and were fed after the 1.5 h postadministration sampling.…”

Pharmacokinetics and bioequivalence of two cyclosporine oral solution formulations in cats

“…In this study, blood pharmacokinetic parameters were calculated using the non-compartmental analysis model 200 (intravenous or extravascular dosing, linear/log trapezoidal method) in the WinNonlin™ software (version 8.1; Certara USA) and WinNonlin 8.1 was used for bioequivalence analysis. Analysis of variance (ANOVA) was used to calculate a 90% CI for the ratio of the two treatments ( 24 , 25 ).…”

Immunsuppressive Therapie bei Hunden und Katzen. Eigenschaften von Wirkstoffen und ihre Anwendung bei verschiedenen immunvermittelten Erkrankungen

“…Ciclosporin hat in den Kapseln und als Lösung (Cyclavance®) eine sehr ähnliche Bioverfügbarkeit. Somit können beide Formulierungen äquivalent eingesetzt werden, wie eine randomisierte Studie bei 40 gesunden Hunden zeigte (73).…”