Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs.
A series of experiments was conducted to study cyclosporin A (CsA) pharmacokinetics in dogs and the factors influencing variability of blood concentrations. In a first study, influence of feeding on drug absorption and blood profile was evaluated. Administration of CsA as micro-emulsion (ME) formulation with food decreased the bioavailability by 22% and increased the individual variability of drug absorption. In a second study, pharmacokinetic profiles from laboratory fasted beagle dogs receiving orally CsA ME formulation were analyzed. CsA was measured in blood samples by high-performance liquid chromatography (HPLC, 34 profiles) and fluorescent polarization immunoassay (FPIA, 16 profiles). A two-compartment model with first-order absorption was used to calculate the pharmacokinetic parameters. Using FPIA, blood concentrations were 1.5 to 1.7 times higher than when using HPLC, but elimination half-life and MRT were similar. The coefficient of variation of key pharmacokinetic parameters ranged from 27 to 34% following HPLC assay. The same range of variation was obtained after FPIA assay. In a third study, in a clinical trial evaluating CsA for the treatment of canine atopic dermatitis, a single blood sample was collected in dogs which had received CsA for 28 days. No significant correlation was found between clinical improvement and CsA blood concentrations. Considering the large margin of safety of CsA in dogs, the limited inter-individual variability and the lack of correlation between blood concentrations and clinical response, routine monitoring of blood CsA does not appear necessary in dogs with atopic dermatitis.
Novartis Animal Health, WRO-1032 2.50, CH-4002 Basle, Switzerland. jean-steffan@ah.novartis.com
J
J
Steffan
G
G
Strehlau
M
M
Maurer
A
A
Rohlfs
D000284:Administration, Oral; D000818:Animals; D002214:Capsules; D002851:Chromatography, High Pressure Liquid / Q000662:veterinary; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003876:Dermatitis, Atopic / Q000188:drug therapy / Q000662:veterinary*; D004283:Dog Diseases / Q000188:drug therapy* / Q000473:pathology; D004285:Dogs / Q000378:metabolism*; D004655:Emulsions; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D016896:Treatment Outcome
D002214:Capsules; D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine