title: Agreement between two methods for assessing bioequivalence of inhaled salbutamol.
abstract: For inhaled medications, bioequivalence testing is becoming increasingly important owing to the availability of many inhalation devices. We evaluated agreement between the Finney bioassay and the Emax model in the assessment of bioequivalence of salbutamol administered via a metered-dose inhaler with a spacer (pMDI+ Volumatic) or via a dry-powder inhaler (Diskus) in asthmatic patients with methacholine-induced bronchoconstriction. Eighteen patients inhaled methacholine until FEV 1 decreased by approximately 35% of control. Following inhalation of placebo, 200 and 400 mcg salbutamol through the pMDI+ Volumatic or the Diskus, changes in FEV 1 were repeatedly measured over a 60-min observation period. Bioequivalence of salbutamol administered via the two inhalation devices was assessed by calculating the relative potency of each device by using the Finney 2-by-2 parallel regression analysis and the non-linear, Emax model. Agreement between these methods in calculating relative potency was evaluated by using the Bland-Altman method. After salbutamol FEV 1 values were similar irrespective of the device employed, and greater (P<0.01) than those after placebo. However, assessment of relative potencies obtained with both the Finney (1.97, 90% CI 1.62-2.32) and the Emax (2.25, 90% CI 1.90-2.60) methods revealed that twice the salbutamol dose was needed to reverse methacholine-induced bronchoconstriction when the drug was inhaled via the Diskus than via the pMDI+ Volumatic. The mean difference in relative potency (-0.28, 90% CI -0.001 to -0.56) calculated with both methods did not significantly differ from zero, and none of the individual differences exceeded the limits of agreement. The Finney and the Emax methods provide comparable results in the evaluation of bioequivalence of different salbutamol formulations. The pMDI+ Volumatic is twice as efficient as the Diskus in lung delivery of salbutamol in asthma patients.
authors.affiliation: Dipartimento di Area Critica Medico Chirurgica, Unità Funzionale di Medicina Respiratoria, Università degli Studi di Firenze, Viale G B Morgagni 85-50134, Firenze, Italy. f.lavorini@dac.unifi.it
authors.forename: Federico
authors.initials: F
authors.lastname: Lavorini
authors.forename: Pietro
authors.initials: P
authors.lastname: Geri
authors.forename: Gianna
authors.initials: G
authors.lastname: Camiciottoli
authors.forename: Massimo
authors.initials: M
authors.lastname: Pistolesi
authors.forename: Giovanni A
authors.initials: GA
authors.lastname: Fontana
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D016210:Methacholine Chloride; D011208:Powders; D013147:Spirometry; D013810:Therapeutic Equivalency
chemical_list: D001993:Bronchodilator Agents; D011208:Powders; D016210:Methacholine Chloride; D000420:Albuterol