Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients

Severe asthmatics treated with oral/inhaled corticosteroids are at risk of side effects (adrenal suppression). Oral cyclosporin A has been effective i n asthma treatment, and nebulized cyclosporin A has been administered for s imilar to 6 months with no nephrotoxicity or hepatotoxicity, suggesting a w ider therapeutic margin for an inhaled cyclosporin A for treatment of asthm a. Single- and repeated-dose studies in healthy and asthmatic male and fema le subjects were conducted to determine the pharmacokinetics, pharmacodynam ics, and safety of a new formulation of inhaled cyclosporin A (ADI628) mete red-dose inhaler (MDI). ADI628 had roughly dose-linear increases in blood c oncentrations with moderate variability after single and multiple administr ation in healthy subjects. Steady-state ADI628 concentrations reflected an effective half-life of 7.0 to 12.5 hours. No overt gender-related differenc es were observed after single inhaled 10 mg ADI628 dose. However, asthmatic s and females (20 mg dose group) had lower ADI628 concentrations as compare d to healthy males, probably due to lower inspiratory flow rates and probab ly not due to disease- or gender-related differences in metabolism/eliminat ion ofADI628. Renal excretion was a minor route of elimination for ADI628 w ith no dose- or gender-related differences. The blood ADI628 exposure in hu mans was 1/3- to 1/6-fold lower than the no-effect dose in dogs. Also, the blood ADI628 exposure after the highest inhaled dose was much lower than af ter the administration of the efficacious oral cyclosporin A dose (3 mg/kg) for treating asthma. The highest steady-state dose (10 mg bid) resulted in ADI628 concentrations that are not typically associated with systemic neph rotoxicity or immunosuppression. furthermore, repeated inhaled doses of ADI 628 were safe and generally well tolerated with no apparent systemic immuno suppressive activity in healthy and asthmatic subjects. (C)2000 the America n College of Clinical Pharmacology.