Influences on plasma cortisol of different formulations of beclomethasone dipropionate

We have previously reported data in 10 healthy volunteers in a crossover design showing significantly greater systemic bioavailability of hydrofluoroalkane (HFA-134a) beclomethasone dipropionate (BEC) compared with the chlorofluorocarbon (CFC) formulation after administration of a 1000-µg nominal dose (ex-valve) from a pressurized metered dose inhaler (pMDI) in healthy volunteers [1]. For the maximal plasma concentration (C_max) this amounted to 1.9-fold greater plasma levels of beclomethasone-17-monopropionate following BEC-HFA (Belcazone CFC-free, Norton Healthcare) than BEC-CFC (Beclazone, Norton Healthcare). We have now retrospectively analysed the same blood samples for plasma cortisol in order to assess whether there are differences in systemic bioactivity between these two formulations

Plasma cortisol concentrations were measured at predose, 0.5, 1, 2, 4, 6, 8, 10 and 12 h after dosing with each formulation. All assays were performed in duplicate in a blinded fashion. Plasma cortisol was measured using a radioimmunoassay kit which has no cross-reactivity for beclomethasone dipropionate or beclomethasone-17-monopropionate (Incstar Limited, Wokingham, Berkshire). The coefficient of variability for the analytical and precision for within assay was 4.3% and for between assay was 7.2%. The cortisol data were not normally distributed and so data are expressed as medians and interquartile ranges, and comparisons were made using the Wilcoxon signed rank test.

At baseline median (interquartile range) values for plasma cortisol were: 546.0 nmol l⁻¹ (497.1–611.3) for BEC-CFC and 544.0 nmol l⁻¹ (510.1–620.0) for BEC-HFA. At 8 and 10 h after inhalation, the differences between HFA and CFC formulations were significant (P < 0.05). Plasma cortisol at 8 h was 83 nmol l⁻¹ (68–93) for BEC-CFC vs 57 nmol l⁻¹ (42–68) for BEC-HFA. Plasma cortisol at 10 h was 138 nmol l⁻¹ (93–165) for BEC-CFC vs 60 nmol l⁻¹ (49–99) for BEC-HFA. The 90% confidence interval for difference in percentage change from baseline (i.e. for BEC-HFA – BEC-CFC) at 8 h was (−12.9 to −0.6%), and at 10 h was (−17.1 to −0.4%).

Our data confirm that pharmacokinetic differences in terms of systemic bioavailability between HFA and CFC formulations of beclomethasone dipropionate were associated with significant pharmacodynamic differences in cortisol suppression. This could have implications for systemic safety when directly switching from BEC-CFC to BEC-HFA at microgram equivalent nominal doses, as recommended by the manufacturer of the BEC-HFA formulation (Norton Healthcare). These data are however, limited because cortisol suppression was only evaluated over a 12 h period and a 24h plasma cortisol profile is required to characterize fully the relative degree of adrenal suppression with these two products. Also our data were from healthy volunteers and so we may not be able to extrapolate to what happens in asthmatic patients, where effects of small airway calibre may reduce lung bioavailability. Finally, we only looked at single dose effects and so it would also be important to evaluate effects at steady-state in order to reflect the real-life situation of repeated twice daily dosing.