Budesonide/salmeterol in fixed-dose combination for the treatment of asthma

Abstract

Fixed dose combinations (FDC) of inhaled corticosteroid (ICS) and long-acting beta agonist (LABA) are well established in asthma treatment. The budesonide/salmeterol (B/S) FDC is now about to reach the market. It is provided as powder in hard capsules of two strengths: 120/20μg and 240/20μg when expressed as delivered doses, equivalent to 150/25μg and 300/25μg when expressed as nominal doses. Its development involved 9 pharmacokinetic (320 subjects), 3 phase II (123 subjects) and 4 phase III (1206 patients with different asthma severity) studies. Delivery is effectuated via low resistance inhaler device, Axahaler®, generating also fine particles targeting the small airways. B/S safety, assessed in 1401 subjects, did not outline novel concerns specific for this FDC. In conclusion, the B/S dry powder FDC can be used for asthma treatment in adults not adequately controlled on ICS alone, or to maintain control of ICS/LABA treated patients, in whom switching to alternative FDC is indicated.

KEYWORDS:

• Asthma treatment
• inhaled corticosteroid
• long-acting beta-agonist
• budesonide
• salmeterol
• fixed dose combination
• inhaler device
• fine particles dose

Financial & competing interests disclosure

The development of the fixed dose combination described in the manuscript has been funded by Belgian based company Laboratories SMB s.a ; the manuscript itself is part of this development. TA Popov is acting as scientific advisor to COMAC MEDICAL, which was contracted by Laboratories SMB s.a., Brussels, Belgium, to carry out several of the phase II and phase III studies for the development of the B/S FDC. In this capacity TA Popov has an insight into the objectives and train of events leading to the preparation of the product for licensing. S De Niet and F Vanderbist are employees of Laboratories SMB s.a. COMAC MEDICAL have contracted professional statisticians and technical personnel for data analysis, statistical analysis, data collection, and data management in separate studies during the > 10 year period of product development. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

The pharmaceutical development program of budesonide/salmeterol (B/S) demonstrated that the administration of an improved formulation (a patented mixture of budesonide and salmeterol blended with anhydrous lactose (main carrier) and lactose monohydrate (carrier of small particles)) through an optimal delivery system (a low airflow resistance capsule-based dry powder inhalation device) results in

• Lower nominal and delivered doses of budesonide than those achieved from the marketed mono and combined therapies (Pulmicort® and Symbicort® Turbuhaler®), leading to a similar lung deposition profile at the optimal flow of each device.

• Lower airflow dependency of budesonide from B/S than from the Turbuhaler device, resulting in a higher fine particle dose from B/S versus the marketed products at lower inhalation airflows.

• Lower variability in the delivery of dose of budesonide from B/S than from the Turbuhaler device.

• Lower nominal and delivered doses of salmeterol than those achieved from the marketed monotherapy, leading to a similar lung deposition profile at all tested airflows.

• Comparable efficacy of the two fixed-dose combinations of B/S, 150/25 μg and 300/25 μg, for periods of time between 12 and 24 weeks with monoproducts and combinations containing the B/S ingredients.

• Sustained efficacy of B/S over the course of 1 year.

• Similar safety results were observed for B/S and the reference therapies, as well as for the two dosages of the B/S combination.