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The meta-analysis by Hughes et alwas hindered by difficulties in comparing trials that were often flawed and of varied design.1 The authors correctly pointed out that, in most of the studies, the use of equivalence as the null hypothesis was invalid. In addition, all but two of the studies looked at the bronchodilator effects in the presence of basal airway tone, when the top of the dose response curve for bronchodilator response occurs in mild to moderate asthma at a salbutamol dose of approximately 200 μg for chlorofluorocarbon (CFC) or hydrofluoralkane (HFA) pressurised metered dose inhalers (pMDIs).2 To construct a proper dose response curve to estimate relative bronchodilator potency would therefore necessitate the use of doses much lower than 200 μg or evaluation of patients with more severe asthma. Two of the cited studies evaluated functional antagonism against histamine induced bronchoconstriction in patients with mild to moderate asthma. However, in such patients the dose response curve for bronchoprotection is relatively shallow. For example, in a recent study of 72 patients with mild to moderate asthma a fourfold increment in the dose of formoterol Turbohaler (from 6 μg to 24 μg) only resulted in a shift in methacholine hyperresponsiveness of one doubling dose.3
One simple way of evaluating bioequivalent doses of inhaled salbutamol is to evaluate the relative respirable lung dose, which can be quantified as lung bioavailability from the early lung absorption profile in the first 20 minutes after inhalation, expressed as the maximal plasma concentration (Cmax), for the same nominal dose.
We have therefore reviewed eight studies performed in our laboratory using an identical design in which a nominal dose of 1200 μg salbutamol was administered via different devices in healthy volunteers.4-11 Where the same device was evaluated in two or more studies, the highest value for Cmax was used. A significant difference between devices was assumed where respective 95% confidence intervals did not overlap. The results are shown in fig1.
There were no differences in lung dose between CFC-pMDI, HFA-pMDI, and the dry powder inhalers, although the Accuhaler produced lower levels than the Diskhaler. As expected, the addition of a Volumatic spacer increased the lung delivery for both CFC-pMDIs and HFA-pMDIs. When used in combination with a Volumatic spacer there was greater delivery with HFA than with CFC. The Sidestream nebuliser resulted in a lower relative lung dose than any of the other devices. However, if an adjustment is made to reflect the usual 2500 μg nominal dose administered by nebuliser (Cmax = 2.52 ng/ml), the lung dose is similar to the adjusted value for a 400 μg nominal dose from a Nebuhaler spacer with HFA-pMDI (Cmax = 2.96 ng/ml).
Although decreased airway calibre in asthmatic patients will reduce the lung dose of salbutamol from a given device,12 the relative difference in lung bioavailability between devices will remain the same and is related to the bronchodilator response.13
Measurement of the lung bioavailability of salbutamol in healthy subjects may therefore represent a simple in vivo method for preliminary quantification of the relative lung dose from different inhaler devices to select rational doses for subsequent clinical equivalence studies in asthmatic patients.
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