title: Tolerability of high cumulative doses of the HFA modulite beclomethasone dipropionate/formoterol combination inhaler in asthmatic patients.
abstract: The corticosteroid beclomethasone dipropionate (BDP) has been formulated with the long acting beta agonist formoterol (BDP/formoterol 100 microg/6 microg, Foster) in a single inhaler using Modulite technology. We have investigated the acute tolerability of high, cumulative doses of BDP/formoterol compared to formoterol alone and placebo. This was a double blind, 3-way cross-over comparison of 10 puffs of BDP/formoterol 100 microg/6 microg or formoterol 6 microg or placebo during maintenance treatment with BDP/formoterol two puffs per day. Pharmacokinetics over 12h during maintenance treatment was measured on day 7. High cumulative doses were then administered on three separated days. Eighteen patients with asthma were recruited (mean FEV(1) 65% predicted). The primary endpoint was serum potassium over the 12h period after high doses. QTc, blood pressure and heart rate over 12h, and plasma lactate and glucose over 3h following dosing were assessed. Formoterol caused a significantly greater decrease in serum potassium than BDP/formoterol or placebo (difference in mean minimum concentrations; 0.11 and -0.15 mmol/l, respectively, p<0.05 for both comparisons). No significant differences in serum potassium parameters were found between BDP/formoterol and placebo. QTc, plasma lactate and vital signs values observed with the combination were not statistically different from those with formoterol alone. For glucose, the mean maximum increase after formoterol treatment was 0.4 mmol/l (p<0.01 compared to placebo), while BDP/formoterol treatment caused a maximum increase of 0.7 mmol/l (p<0.01 compared to formoterol and placebo). The active metabolite of BDP is beclomethasone-17-monopropriate (B17MP), which reached Cmax at 0.25 h, with an elimination half-life of 3.7 h. Formoterol also reached Cmax at 0.25 h, and concentrations were measurable up to 12 h. High doses of BDP/formoterol did not significantly reduce serum potassium, while formoterol alone did to a greater extent. The BDP/formoterol combination was well tolerated, and exhibited a safety profile generally similar to formoterol alone when administered in high doses to stable asthmatic patients.
authors.affiliation: Medicines Evaluation Unit, South Manchester University Hospitals Trust, University of Manchester, Southmoor Road, Wythenshawe, Manchester M23 9QZ, UK. dsingh@meu.org.uk <dsingh@meu.org.uk>
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.forename: Annalisa
authors.initials: A
authors.lastname: Piccinno
authors.forename: Zoe
authors.initials: Z
authors.lastname: Borrill
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Poli
authors.forename: Daniela
authors.initials: D
authors.lastname: Acerbi
authors.forename: Luc
authors.initials: L
authors.lastname: Meuleners
authors.forename: Ashley
authors.initials: A
authors.lastname: Woodcock
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001507:Beclomethasone / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D004562:Electrocardiography; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D000068759:Formoterol Fumarate; D006207:Half-Life; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood
chemical_list: D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D004338:Drug Combinations; D004983:Ethanolamines; D019344:Lactic Acid; D001507:Beclomethasone; D011188:Potassium; D000068759:Formoterol Fumarate