Adrenal effects and pharmacokinetics of CFC-free beclomethasone dipropionate: a 14-day dose-response study

Since equivalent efficacy is achieved with lower doses of the reformulated beclomethasone dipropionate in the chlorofluorocarbon (CFC)-free propellant HFA-134a (HFA) than with the original CFC-beclomethasone dipropionate form ulation, it is possible the HFA-beclomethasone dipropionate may have less s afety concerns than the CFC formulation. Despite its chronic use, the stead y-state pharmacokinetics of beclomethasone dipropionate has never been stud ied before. This double-blind study examined adrenal effects and pharmacoki netics after 14 days of dosing with HFA-beclomethasone dipropionate. Forty-three steroid-naive asthmatic patients were randomised into 5 paralle l groups and dosed every 12 h for 14 days with: HFA-placebo; 200, 400 or 80 0 mu g day(-1) HFA-beclomethasone dipropionate; or 800 mu g day(-1) CFC-bec lomethasone dipropionate. After two weeks of dosing, the 24-h urinary free cortisol of all but one patient remained within the normal range, showing t hat all doses were well tolerated from a systemic safety perspective. The a ctive HFA-beclomethasone dipropionate treatment groups showed a dose-relate d fall in 24-h urinary free cortisol. Total-beclomethasone (beclomethasone dipropionate and metabolites) pharmacokinetics after either the first dose of HFA-beclomethasone dipropionate or CFC-beclomethasone dipropionate were not substantially affected by subsequent doses. The extent of drug absorpti on from 800 mu g day(-1) HFA-beclomethasone dipropionate and CFC-beclometha sone dipropionate was in the ratio of 1.7:1. A non-linear correlation betwe en 24-h urinary free cortisol and the pharmacokinetic parameters was observ ed, reflecting smaller changes in 24-h urinary free cortisol than in pharma cokinetics as the dose was increased. No clinically meaningful change in the pharmacokinetics of beclomethasone d ipropionate plus metabolites was seen on multiple dosing. The greater syste mic availability of HFA-beclomethasone dipropionate was still associated wi th adrenal effects comparable with that of the CFC formulation at the same dose.