SOPROBEC Pressurised inhalation solution Ref.[27642] Active ingredients: Beclometasone

Beclometasone dipropionate is a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclometasone-17-monopropionate which has a more potent topical anti-inflammatory activity compared with the pro-drug beclometasone dipropionate.

Absorption when administered via inhalation by a MDI

Systemic absorption of unchanged beclometasone dipropionate (BDP) occurs through the lungs. There is negligible oral absorption of the swallowed dose of unchanged BDP. Prior to absorption there is extensive conversion of BDP to its active metabolite B-17-MP. The systemic absorption of B-17-MP arises from both lung deposition (36%) and oral absorption of the swallowed dose (26%). The absolute bioavailability following inhalation is approximately 2% and 62% of the nominal dose for unchanged BDP and B-17-MP, respectively. BDP is absorbed rapidly with peak plasma concentrations observed (t_max) at 0.3 hours. B-17-MP appears more slowly with a tmax of 1 hour. There is an approximately linear increase in systemic exposure with increasing inhaled dose. When administered orally the bioavailability of BDP is negligible but pre-systemic conversion to B-17-MP results in 41% of the dose being absorbed as B-17-MP.

Distribution

The tissue distribution at steady-state for BDP is moderate (20 L) but more extensive for B-17-MP (424 L). Plasma protein binding is moderately high (87%).

Biotransformation

BDP is cleared very rapidly from the systemic circulation, by metabolism mediated via esterase enzymes that are found in most tissues. The main product of metabolism is the active metabolite (B-17-MP). Minor inactive metabolites, beclometasone-21- monopropionate (B-21-MP) and beclometasone (BOH), are also formed but these contribute little to the systemic exposure.

Elimination

The elimination of BDP and B-17-MP are characterised by high plasma clearance (150 L/hour and 120 L/hour) with corresponding terminal elimination half-lives of 0.5 hours and 2.7 hours. Following oral administration of tritiated BDP, approximately 60% of the dose was excreted in the faeces within 96 hours mainly as free and conjugated polar metabolites. Approximately 12% of the dose was excreted as free and conjugated polar metabolites in the urine. The renal clearance of BDP and its metabolites is negligible.

Special populations

The pharmacokinetics of beclometasone dipropionate in patients with renal or hepatic impairment has not been studied; however, as beclometasone dipropionate undergoes a very rapid metabolism via esterase enzymes present in intestinal fluid, serum, lungs and liver, to originate the more polar products beclometasone-21-monopropionate, beclometasone-17-monopropionate and beclometasone, hepatic impairment is not expected to modify the pharmacokinetics and safety profile of beclometasone dipropionate.

As beclometasone dipropionate or its metabolites were not traced in the urine, an increase in systemic exposure is not envisaged in patients with renal impairment.

Preclinical safety studies indicate that beclometasone dipropionate shows negligible systemic toxicity when administered by inhalation.

The non-CFC propellant HFA-134a has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of up to two years.