Local versus Total Systemic Bioavailability of Beclomethasone Dipropionate CFC and HFA Metered Dose Inhaler Formulations

Abstract

For inhaled formulations, the balance between desired local effects and undesired systemic activity can be expressed by L/T, where L represents bioavailability of drug from the lungs and T represents total systemic bioavailability. L/T is most useful when comparing formulations of the same inhaled substance. A high L/T is desirable as this implies efficient drug delivery to the target site, and minimization of unwanted activity from non-targeted drug delivery. The objective of this publication is to compare L/T for CFC and HFA inhaler formulations of beclomethasone dipropionate (BDP). Predictions of the L/T comparison were tested with clinical trials. From five deposition and pharmacokinetic studies, L/T ratios for CFC-BDP and HFA-BDP were calculated as 0.21 and 0.92, respectively. These ratios predicted two differences for the therapeutic use of these products: (1) a smaller dose of HFA-BDP than CFC-BDP may be required for efficacy; and (2) a smaller number of adverse events may be observed for the HFA-BDP product, when delivered at the equivalent dose, compared to the CFC comparitor. A dose-response study confirmed that less than half the dose of HFA-BDP is needed to give the same efficacy as CFC-BDP. Two safety studies that measured adrenal suppression demonstrated less suppression with HFA-BDP than with a comparable efficacious dose of CFC-BDP. It is concluded that L/T is a useful parameter that incorporates the systemic contributions of lung deposition and pharmacokinetics. It is recommended that this parameter be considered whenever deposition and pharmacokinetic data for two formulations of the same inhaled substance are compared.