Assessment of a relative therapeutic index between inhaled formoterol and salbuterol in asthma patients.
OBJECTIVE
To quantify the relation between local and systemic magnitudes of effects of inhaled formoterol and salbutamol.


METHODS
Twenty-eight stable asthmatic patients completed this double-blind, randomised crossover study. Pre-drug administration FEV1 (mean 2.08 L) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutanmol. Patients inhaled three single doses of formoterol fumarate dihydrate (Oxis) (delivered doses of 4.5, 18 and 54 microg) via Turbuhaler, two single doses of salbutamol (200 and 1800 microg) via a pressurised metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. A classic sigmoid model of log-dose response was used to discriminate pharmacologically between formoterol and salbutamol. Relative local (maximum FEV1) and systemic (minimum S-KC) dose potencies, and their ratio, the relative therapeutic index, were estimated using an on-linear mixed effect model.


RESULTS
The drug effects were well tolerated and dose dependent The bronchodilating effect was on a part of the dose response curve that could be well approximated by a log-linear function, the serum potassium suppressing effect sometimes was not (the lowest doses differed only marginally from placebo). Thus, a log-linear approximation was used to describe bronchodilation, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index was estimated to be 2.5 (95%confidence interval: 0.9-6.5).


CONCLUSIONS
The mean relative therapeutic index between formoterol (Oxis) 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to 2.5 in favour of formoterol; this trend was not statistically significant.
Rosenborg
Johan
J
Experimental Medicine, AstraZeneca R&D Lund, Sweden. Johan.Rosenborg@astrazeneca.com
Larsson
Per
P
Rott
Zsuzsanna
Z
Böcskei
Csaba
C
Poczi
Magdolna
M
Juhász
Gábor
G
D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004983:Ethanolamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D011188:Potassium / Q000097:blood
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D000420:Albuterol; D011188:Potassium; D000068759:Formoterol Fumarate