INTRODUCTION

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In response to the requirement to phase out chlorofluorocarbon (CFC)-containing aerosol inhalers, a number of different pressurized aerosols incorporating non-CFC propellants and various dry powder devices have been developed. As part of the intensive research programs investigating the performance of these novel inhalation devices, it is necessary to compare their efficacy with that of the established CFC-containing pressurized metered dose inhalers (pMDIs) currently used. For ₂-agonists, this involves determining their relative dose-potency through examining their dose-bronchodilator response relationships. Traditionally this has been done by employing a cumulative dose-response design similar to that proposed by Shenfield and Paterson (1), in which each device or drug is tested during a single day by giving sequentially increasing doses. Alternatively, comparison of the bronchodilator response to different doses given on separate days has been undertaken (2).

When a dose-response curve for an inhaled ₂-agonist is obtained using the single-dose separate day design, a well- defined plateau indicating the top of the dose-response curve is seen at dose levels within the range of that normally given to patients as a single dose (2). When the same drug is given cumulatively during a single day, however, a continuous increase in elicited effect is seen, rather than a plateau, even at doses higher than the normal clinical doses (7). This phenomenon is not fully understood, but it may relate to increasingly more peripheral deposition obtained after the initial dose of the inhaled drug. It could also be that the inhalation maneuver contributes to the bronchodilating effect, or that part of the increased response to cumulative dosing is due to a delayed effect of the initial doses.

One approach to evaluate the validity of the cumulative design would be to perform a cumulative study with two different, predetermined doses of a ₂-agonist. The same number of inhalations would be given on each study day, with the only difference during active treatment being the two doses. If the difference in doses is not reflected in a difference in elicited effects, the cumulative design cannot be considered valid for the comparison of different formulations of a ₂-agonist.

Objective of the Study

The primary objective of the present study was to evaluate the cumulative dose study design by comparing the bronchodilating effect of salbutamol administered according to a high cumulative dose regimen with that of a low cumulative dose regimen. The secondary objective was to compare the bronchodilating effect of a cumulative dose regimen with that of a single-dose regimen. In addition, the effect of the inhalations per se was investigated by giving placebo in a cumulative manner.

	METHODS

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Patients

Twenty-four adults with asthma (11 men) participated in the study. The mean age of the patients was 31.8 yr (range, 19-59 yr). The inclusion criteria were a baseline forced expiratory volume in 1 s (FEV₁)  40% of the predicted normal value, and a reversibility in FEV₁ of  15% after a single 50-µg salbutamol Turbuhaler (AstraZeneca, Lund, Sweden) dose, with a further FEV₁ increase of  50% of the initial increase after a second 50-µg salbutamol dose administered 30 min later. The stepwise reversibility test aimed to exclude patients who responded well to salbutamol but had a steep dose response over the dose interval to be studied. The mean baseline prebronchodilator FEV₁ was 2.35 L (range, 1.06-3.87 L) corresponding to 66.0% (range, 42.5-93.7%) of predicted normal values. The mean FEV₁ was 2.89 L (range, 1.32-4.63 L) after the first inhalation of 50 µg of salbutamol and 3.23 L (range, 1.47-5.05 L) after the second. The mean reversibility after the first inhalation was 23.8% (range, 15.0-53.8%) and the mean additional increase after the second inhalation, expressed as a percentage of the first increase, was 66.1% (range, 50.0-100.0%).

The study was approved by the Wellington Ethics Committee and all patients gave written informed consent.

Study Design

The study was of a double-blind, double-dummy, randomized, cross-over design. There were five clinic visits, Visit 1 being an enrollment visit at which reversibility was assessed. On the four active days (Visit 2-5), the patients received, in a randomized order, each of the following dose regimens:

A: 50+50+100+200 µg of salbutamol via Turbuhaler (400-µg cumulative dose)

B: 100+100+200+400 µg of salbutamol via Turbuhaler (800-µg cumulative dose)

C: 400+0+0+0 µg of salbutamol via Turbuhaler (400-µg single dose)

D: Placebo (0+0+0+0 µg) via Turbuhaler

The four doses on each treatment day were administered at 30-min intervals. Treatments A-D were double-blinded, using Turbuhaler placebo inhalers; active inhalation was performed first. Study days were separated by a washout period of at least 1 d. All inhalations were made by administering either salbutamol (50 or 100 µg) or placebo by Turbuhaler. On each treatment day there was a requirement for the baseline FEV₁ to be within 15% of the Visit 1 baseline value. If the baseline FEV₁ value was not within 15% of the Visit 1 baseline, the visit was rescheduled once. FEV₁ was measured before the first drug administration and then 5 and 25 min after each dose, and again 55 and 85 min after the last dose. The FEV₁ was measured on a Vitalograph alpha spirometer (Vitalograph, Buckingham, UK), with a single measurement made at each time point.

Statistics

To estimate the relative dose-potency between the cumulative high- and low-dose regimens, data collected 5 min (and in a separate analysis 25 min) after each dose increment were used. Data were first reduced to means and covariances by a multiplicative analysis of variance (ANOVA) model with factors patient, visit, treatment, dose, and interaction treatment by dose. Parallel regression lines were fitted to the means and the relative dose-potency estimated by the shift of these dose-response lines. Confidence limits were constructed using Fieller's theorem.

Comparisons between the four treatment regimens were also made for E_{5 min} (the value 5 min after the first dose), E_{25 min}, E_{115 min}, E_max (the maximum FEV₁ value during the 90-min measurement period after the last drug inhalation), and E_av (the average FEV₁ value during the same period). These were made using a multiplicative ANOVA model with factors patient, visit, and treatment, and 95% confidence intervals were constructed for the pairwise treatment ratios. In addition, the mean FEV₁ time curve for each of the four treatment regimens (expressed as percentage change from baseline) was plotted on a single graph.

	RESULTS

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All treatment regimens were well tolerated and no adverse events were reported. The mean changes in FEV₁ from baseline for each treatment regimen are shown in Figure 1. The mean baseline FEV₁ was similar on the four days (Table 2). The mean (range) number of days between each treatment visit was 5.8 (1) d. Curves for the three active treatment regimens were similar until Dose 2, after which the cumulative dose regimens resulted in further increases in FEV₁, whereas no additional effect was obtained from the subsequent three placebo inhalations associated with the 400-µg single-dose regimen. For the 400-µg single-dose curve, the first dose produced an increase in FEV₁ that reached its maximum at about 30-40 min after dosing. The increase in FEV₁ after the first inhalation of placebo resulted in a bronchodilation that was maximal after 30-40 min with no additional effect from subsequent placebo inhalations.

View larger version (22K): [in this window] [in a new window]   Figure 1.   The mean change in FEV1 from baseline for each treatment regimen.

Comparisons between the Cumulative Dose Regimens

The two cumulative dose regimens produced almost identical bronchodilating responses at each time point (Figures 1 and 2). For both cumulative treatment regimens, each new dose produced an increase in FEV₁, suggesting that the dose-response plateau had not been reached. The relative dose-potency between the 800- and 400-µg cumulative dose regimens (note the dose order: 800 µg/400 µg) was 0.7 with a 95% confidence interval of 0.5-1.0, indicating that the higher cumulative dose was not more potent than the lower cumulative dose.

View larger version (12K): [in this window] [in a new window]   Figure 2.   The mean FEV1 5 min after each dose for the 800- and 400-µg salbutamol cumulative dosing regimens.

Comparisons between Single Doses

There was no difference in the bronchodilating response to single doses of 50, 100, or 400 µg of salbutamol via Turbuhaler after either 5 or 25 min (Table 1). All active treatments gave significantly higher values than placebo.

Comparisons of E_max and E_av

Over the interval of 90 to 180 min after the final dose, all active treatments gave significantly higher E_max and E_av values than placebo (Table 2). The difference in E_max and E_av values did not reach significance for the 800-µg cumulative dose compared with the 400-µg single-dose regimen. However, the E_max and E_av values were significantly greater for the 400-µg cumulative dose regimen compared with the 400-µg single-dose regimen.

Comparison between Cumulative and Single-Dose Regimens

The mean percent change in FEV₁ from baseline at 25 min after each dose for the 400-µg cumulative dose regimen was greater than that after the corresponding single (first) dose (i.e., 50-, 100-, and 400-µg single dose) (Figure 3). The FEV₁ value measured 115 min after the first inhalation for the 400-µg cumulative dose regimen was higher than that for the 400-µg single-dose regimen measured at 115 min (3.12 versus 2.91 L, p = 0.02). The FEV₁ value measured at 115 min for the 400-µg cumulative dose regimen was higher than that for the 400-µg single-dose regimen at 25 min (3.12 versus 2.90 L, p = 0.006), that is, the values measured at equal times after the last active inhalation.

View larger version (13K): [in this window] [in a new window]   Figure 3.   The mean change in FEV1 from baseline 25 min after each dose for the 400-µg cumulative regimen and the three single-dose regimens.

There was no difference in the bronchodilating response to the single dose of 50, 100, and 400 µg of salbutamol via Turbuhaler after either 5 or 25 min (Table 1). All active treatments gave significantly higher values than placebo.

	DISCUSSION

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The major finding of this study was that when salbutamol was inhaled by subjects with asthma, a 400-µg cumulative dose regimen administered over 90 min resulted in increases in FEV₁ almost identical to those from an 800-µg cumulative dose regimen, given with the same number of doses over the same time interval. This suggests that, in a group of asthmatic patients with marked bronchodilator responsiveness to ₂-agonist therapy, a same-day cumulative study design may fail to detect a difference in ₂-agonist dose-potency even where a true difference exists (20).

These findings suggest that conclusions cannot be drawn from comparative cumulative dose studies in which no differences between devices, or different ₂-agonists through the same device, have been observed (7, 12, 19, 21). An example is that of the study by Mellén and coworkers, in which the authors concluded that the efficacy of salbutamol was "comparable when the drug is given via the Turbuhaler or pMDI" as the two cumulative curves coincided (19). In the light of the present information, this could be a false conclusion, because a significant within-inhaler dose-response relationship is not sufficient to conclude that the study is able to distinguish between the investigated devices, if a true difference in relative dose-potency exists. Conclusions with respect to the relative dose-potencies of the investigated drugs and/or devices can be made only if, in addition, significant shifts between the cumulative dose-response curves can be shown (15, 17, 18, 26). There is no apparent explanation as to why some but not other studies have shown significant differences in cumulative dose-response curves, in terms of study design, doses administered, patient selection, or methods of assessment.

Another objective of the study was to compare the effect on FEV₁ of inhaled salbutamol administered using either a cumulative dose regimen or the equivalent single dose. This comparison showed that the bronchodilating response after 400 µg administered over a 90-min period was greater than that after a 400-µg single-dose administration. This finding is consistent with previous studies in which a difference in response after cumulative and single-dose regimens has been shown (27, 28). For example, Heimer and coworkers (27) reported that the increase in FEV₁ after the first inhalation was similar for single 0.65- and 1.95-mg doses of metaproterenol. However, there was a further increase in FEV₁ at 20 and 30 min when additional 0.65-mg doses of metaproterenol were given, on top of the initial 0.65-mg dose, after 10 and 20 min, according to a cumulative design. Similar findings were reported by Britton and Tattersfield (28), who observed that the bronchodilator response to isoprenaline was less when administered as single doses of 10, 20, 80, and 400 µg when compared with the same doses given according to a cumulative regimen.

These, and the present, results suggest that the observed difference is due to better penetration of aerosol into the airways partially dilated by preceding treatment. The first dose partially opens up the constricted lung, but the dose needed for this "first maximal bronchodilation" is far below the doses usually given. The dose needed to achieve this near-maximal initial effect has been called the "relative saturation dose" (29). The next dose given will reach "new" areas of the lung and thus the bronchodilator effect will increase further. This will eventually result in a dose-response curve that gradually approaches a maximum. The different plateau levels at the different doses will together form a "floating plateau."

Another major finding from the present study was that there was no FEV₁ dose-response relationship associated with single doses of Turbuhaler-administered salbutamol within the range of 50 to 400 µg. The improvement in FEV₁ after a single dose of 50, 100, and 400 µg was similar both 5 and 25 min after inhalation, indicating that 50 µg of salbutamol, given via Turbuhaler, produced a bronchodilation close to the maximum bronchodilation response achievable with a single-dose administration. These findings have important clinical implications with respect to the efficacy of ₂-agonist therapy in asthmatic subjects with marked baseline airflow obstruction and bronchodilator responsiveness. They indicate that the doses of -agonists delivered through modern inhalation devices may be higher than that required by most patients with asthma, and that repeated self-administration of low doses of a -agonist over a period of 30 to 60 min will give a better bronchodilator response than higher doses inhaled as a single administration. In general terms, these findings also support the use of "low-dose" ₂-agonist preparations.

In summary, this study illustrates the major difficulties that exist in the comparison of the bronchodilating efficacy of different ₂-agonists or different ₂-agonist delivery systems. Determining the relative bronchodilating dose-response relationship by utilizing a design based on cumulative doses on the same day has problems similar to those of comparisons using single-dose regimens. We suggest considerable caution in interpreting results from studies that have employed either a cumulative or single-dose design for this purpose, at least unless a significant difference in bronchodilation was observed. Finally, this study provides further evidence that for ₂-agonists such as salbutamol, lower doses than those currently recommended may be used and that repeated self-administration of low doses over a period of 60 min will give a better bronchodilator response that a higher dose administered once.