Bronchodilator Effect of Inhaled Formoterol vs Salbutamol Over 12 Hours

Bronchodilator vs Salbutamol

Effect of Inhaled Formoterol Over 12 Hours*

Francis P. V. Maesen, M.D., Ph.D., F.C.C.P.; joseph]. Smeets; Hendrik L. L. Gubbelmans, M.D.; and 1\m'a G. M.A. Zweers, M.D.

The bronchodilator effects were compared in 16 stable asthma patients for 12 hours after either 12 ..,g formoterol or 200 ..,g salbutamol from a metered-dose aerosol in a randomized, double-blind, crossover study. The FEV, measured before 1, 2, 4, 6, 8, 10 and 12 hours after administration was used as the parameter. From 2 hours onwards after dosage, the bronchodilator effect of formoterol was statistically signi&cantly greater than that of

onnoterol fumarate (Fig 1) is a recently developed F catecholamine analog with a distinct selective and long-acting effect on the beblt-receptors of smooth bronchial muscle. When administered as an oral formulation it produces bronchodilatation lasting for 8 hours or more} In a dose-finding study of3, 6 and 12 J.Lg formoterol metered-dose aerosol, the dose of 12 J.Lg was shown to be superior with regard to maximum bronchodilator effect, onset, and duration of action up to 7 hours. No measurements were performed after this point of time. Side effects, such as tremor were rare. No influence on heart rate and blood pressure was seen. 2 Results from studies performed by Nolte and Meyer.:! yielded similar conclusions. LOfdahl et al4 demonstrated that 6 J.Lg formoterol was equipotent with 100 J.Lg salbutamol; with FEV1 measurements up to 8 hours, a statistically significant difference was *From the Department of Pulmoll8J")' Diseases, De \\\wer Hospital, and the Medical Department, Ciba-Geigy B.V., Arnhem, The Netherlands. Manuscript received Aprill7; revision accepted August 11. Reprint requeats: Dr. Maesen, De Wroer Hoipitol, 6419 PC Heerlen,

Netherlands

salbutamol. The effect of formoterollasted longer, and even after 1! hours, the FEV, was still !0 percent above the baseline value. This is clinically signi&cant and offers new possibilities for treatment of the so-called "morning dip." Both agents were weD tolerated. (Cheat 1990; 91:590-94)

I

AUC=area under curve

I

observed between treatments in favor of formoterol from 4 to 8 hours after administration. To ascertain whether the efficacy of formoterol would last even longer, we performed a study to compare the bronchodilator efficacy of 12 J.Lg formoterol metered-dose aerosol with that of 200 J.Lg salbutamol, also from a metered-dose aerosol, over 12 hours. MATERIAL AND METHODS

In a double-blind, crossover, single dose study, we studied 16 patients in random-permuted blocks of four patients, ages 18 to 70 years, with stable bronchial asthma, who had previously shown an increase in FEV, of 20 percent or more 15 minutes after inhaling 200 ~~og of salbutamol metered-dose aerosol. All patients gave their informed consent for this study, which bad previously been approved by the Institutional Ethical Review Committee. On two study days, separated by one day of rest, patients received either two puffs of 6 ~~og formoterol metered-dose aerosol or two puffs of 100 ~~og matching salbutamol metered-dose aerosol. Baseline FEV, values on these study days were at least 1.0 L and less than 80 percent of the predicted value (based on the guidelines for standardized lung function testing from the European Community for Coal and Steel) with an individual variation of less than 20 percent between the two values. (Iable I). Patients arrived at the outpatient clinic at 9.00

FIGURE I. Structural formula offormoterol.

590

Inhaled Forrnolelol VI Sa1Jutamo1 f"'-' et til)

Taf,le 1-lbtient Charoc~BrVtica* FEV, Age,

Height,

Sex

yr

em

01 02 03

M M

48

04

M M M M M M F F F M M M M

187 188 172 182 170 171 183 168 168 169 165 160 171 187 174 182

Patient No.

05 06 07 08 09 10 11 12 13 14 15 16

~

44 42

34 42

53 62 62

45 60

55 68 50

32

45 35

Weight, kg

Baseline,L

&3

2.55 1.55 1.92 3.49 1.53 1.36 1.57 2.14 1.24

107 86

114 68 90

84 72 86

62 55 68 76 92 64 82

(%pred)

Reversibility

Oral

Inhaled

61

20 51 22 21 26 21 49 20 8i 21 52

be be th, tb

sa, heel heel fe fe, heel, ip fe fe sa, heel, cr sa, heel fe, heel sa, heel sa, heel, cr, ke sa, heel fe sa, heel sa, heel sa, heel

36

52 80 42

41

44

73 36

57

1.50 1.97 1.42

60

1.86

61 48 41

1.22 2.78

64

1.64

Treatment

33

th, be

th

27 23 100 22 24

be be

•be, betamethasohasone; th, theophylline; tb, terbutalin; sa, salbqtamol; becl, heeloPtethasone; fe, fenoterol; ip, ipratropium bromide; cr, cromoglycate; ke, ketotifen. AM. Inhaled beta.-agonist and anticholinergic agents were withheld for 8 hours, oral heta.-agonists fur 24 hours, and slow release theophylline for 36 hours. Patients talcing inhaled/oral corticosteroidS pr cromoglycates con~ued this treabnent at a constant dose throughout the study. Smoking ~d use of caffein~ntaining drinks not allowed during the observation perlod. After 30 minutes of re~. the folloWing baseline Qleasuremeq~ were made usil!g a pulmograph (Sensor Medics):- FEY, FVC, and FEF25-75% during the middle half of the FVC were recorded three ~es and the highest values (BTPS corrected) were used. Pulse rate was measured by counting
wa

FEV1

(~

compared to the baseline value, patients were given two puffs of 100 11-g salbutamol and the length of time between start of the trial and this administration was recorded. Unwanted effects and details of their ~eJity, tim~ of onset, !furation and re~on to the trial treatment were recorded throughout the sl!Jdy days. A wash-out period of 36 hours was then scheduled befOre repeating the test with the other drug, ie, either 12 JLg formoterol or 200 ~~og salb~tamol. The Student's t-test fur paired measurements was used fur statistical com,parison. All statisical tests were carried out as a two-sided test at the 5 percent l~vel (alpha = 0.025).

REsuLTS Characteristics of the 16 patients (13 men and three women) and reversibility on the selection day are shown in Thble 1. Mean age was 48.6 ( ± 10.8} years (range 32 to 68 y~s), mean height 174.8 (±8.7) em apd mean weight 80.6 (±15.9) kg.- Mean baseline

of baaellnel

160r-----~---------------------------------------.

140

130

FlcuRE 2. FEV, after inhalation ofrormoterol, 12~~og(•quara) !Uld salbutamol, 2QO ~~og ( lfar~). is expressed as m8!Ul (SEM) penienb!ge of baseline. Mean baseline F~, formoterol J. 74 L salbutamoll.77 L lOUd bar is reversi- 1 OOII---I..---L.---I..--'---'---'---'----'--------'-------'-------'-------'------' 12 REV 10 68 1 2 4 bility selection day/(pUred Students t-test: 0 TIME (houra) ~<0.05, ••p<0.01, ••~<0.001).

n:v,

CHEST I 97 I 3 I MARCH, 1990

591

FEV 1 on the selection day was 1.86 ( ± 0.62) L, which was 52 ( ± 14) percent of the predicted value. The mean reversibility was 36 ( ± 24) percent. Mean systolic blood pressure was 136.9 (±8.1) mm Hg and mean diastolic blood pressure 83.8 (±5.9) mm Hg. Mean pulse rate was 80.4 (±7.2) per minute. No premature discontinuations were reported and no patient needed any additional puffs during the observation period on either study day.

(±0.81) L, whereas it was 1.79 (±0.70) L after salbutamol. This was a statistically significant difference (p=0.003). On the formoterol day, the mean difference between FEY 1 12 hours after administration vs baseline FEV1 was +0.33 L, and on the salbutamol day, + 0.03 L. This difference between the two treatments was also statistically significant (p=0.001). The AUC over 12 hours was significantly greater for formoterol than for salbutamol (p = 0.003). At the end of the study day, reversibility with 200 J.Lg salbutamol resulted on both treatment days in FEV1 values comparable with reversibility on the selection day.

FEV1

Mean baseline FEV 1 on the formoterol day was 1.74 ( ± 0. 70) L (48 percent of predicted), on the salbutamol day 1. 77 ( ± 0.62) L (49 percent of predicted), which was not statistically significantly different (the range of the individual variation in FEV 1 between the treatment days was 1 to 20 percent). Figure 2 shows the percentage of increase in FEV 1 vs baseline in time. Both drugs produced a rapid increase in FEV 1 within the first hour. The maximum effect with salbutamol was reached after 1 hour, but after formoterol, the FEV 1 continued to rise reaching its peak effect after 2 hours. From 2 hours up to 12 hours after administration, the bronchospasmolytic effect of formoterol in comparison with that of salbutamol (measured as the increase in FEV 1) was significantly to very significantly higher. With formoterol, the FEV 1 was still more than 20 percent above the baseline 12 hours after administration, still a clinically relevant increase of FEV 1 • With salbutamol, the decline below the 20 percent level was reached between 4 and 6 hours after drug intake; after 10 hours, FEV 1 had practically returned to the baseline level. The mean FEV 1 12 hours after administration of formoterol was 2.06

Unwanted Effects

No adverse reactions were reported on either treatment day.

Blood Pressure No clinically relevant changes in mean or individual systolic or diastolic blood pressure could be observed on either treatment day (Table 2 and 3). Pulse Rate

On the formoterol day, as well as on the salbutamol day, the mean pulse rate over the 12 hours decreased by 6 beats per minute. No clinically relevant changes in individual pplse rate was observed (Table 4). DISCUSSION

Early studies with formoterol oral formulation in a dosage of 80 J.Lg indicated a long duration of action of 8 hours; one should take into account, however, that a substantial part of studies performed with this oral

Table 2-Systolic Blood Preuure (mm Hg) Formoterol, Hours After Administration Patient No. 01 02 03 04

05 06

07 08 09

10 11 12 13 14 15 16 Mean

Std

0*) 130 120 120 140 130 140 130 130 145 145 140 135 130 145 130 135 140 134 88

2 125 120 125 135 125 145 130 145 140 145 130 135 140 130 140 135 136

125 125 130 110 135 120 150 140 140 140 145 145 135 145 140 135 145 135 11

4

115 125 125 115 110 135 135 125 120 145 150 135 130 140 130 135 140 140 135 145 130 135 135 135 130 140 140 135 135 135 130 131 134 8 10

*Before administration of trial medication. 592

6

Salbutamol, Hours After Administration 10

8

125 125 125 120 130 130 145 130 125 145 140 140 140 140 130 130 133 8

12

0*)

246

135 125 125 120 130 12o 135 120 125 120 120 120 125 120 130 130 135 135 135 125 150 145 135 125 135 140 145 150 150 145 150 140 140 145 130 140 140 135 130 130 140 140 145 145 145 145 125 150 150 130 135 135 145 135 145 140 140 135 135 125 125 125 135 135 125 125 140 135 145 140 135 135 140 140 145 130 130 145 135 130 135 130 135 136 138 135 133 133 9 10 6 9 9

8

125 125 115

125 130 120 130 140 150 130 130 140 135 140 135 130

10

125 120 120 130 110 115 140 140 140 135 140 145 155 135 125 135 130 140 150 130 130 140 145 145 135 145 135 135 130 140 140 140 140 145 135 140 - 140 145 145 145 140 130 135 140 135 133 134 134 137 138 8 10 10 9

12 120 135 115 140 145 150 140 140 125 140 140 145 145 145 140 10

Table 3-Diaatolic Blood Pn1Baun1 (mm Hg) Formoterol, Hours After Administration Patient No. 01 02 03 04

05 06 07

08 09

10 11

12 13 14 15 16 Mean Std

0*)

12468

90 80 80 80 90

90 85 80 80 80

85 90 80 85 80

100

100

100

85 85 80 80 80 80 85 85 80 85 80 84

90 85 85 80 80 90

75 80 90

75

84

80 90 80 80 90

70 70 90 80

85 80 80 80 80 90 80 90 80 80

80 80

75 80 90 95 80 80 85

75

75

80 80

85 75

75 75

75 85 80

90

75

81 81 6785657697679979 83

Salbutaii!ol, Hours After Administration

10

12

0*)

90 90 80 80 80 80 85 75 85 80 95 100 85 90 85 90 85 85 80 80 85 90 85 90

95 85 80 80 90

90 85 80 80 90

100

100

90 90

80

90

95

75 80 85

75 83

75 75 90 80 84

90 85 85 80 80 95 80

87

75

2468 90 90 90 85 90 85 80 75 75 80 80 85 85 85 80 85 95 95 90 80 85 85 85 85 80 75 80 80

70 75 75 75 75 80

90 80

75

70

90

80 95

100

100

100

100

85 80 80

85 90 90 85

95 90 80 80

70

70

80

75 75

85

85 85

70 75

75 75 75 75

75 75

70 75 75

100 80

90

90

90

90

70 81

85 80

85 85 85 90 90

85 80 85

75 75 82 83

80 80

75 70

90 90

84

12

85

90 90 80 80 85 90

90

10

90 80

90 80

90

90 80

70

70

75

75

83

83

84 84

*Before administration of trial medication.

days in this trial was merely based on previous clinical experience with formoterol aerosol, as well as on the consideration that climatologic influence on the asthma patients should be avoided as much as possible by performing the tests within a short interval. Also, the short half life was taken into account, which was in the range of 1. 7 to 2.3 hours, obtained by measuring the urinary excretion rates and cumulative urinary excretion of the drug. In pharmacokinetic studies in man, it appeared that even with highly sensitive methods, the detection of nonradioactive labelled formoterol in plasma was impossible at an oral dosage below 200 J.Lg. From studies with 3 H-formoterol, it

formulation took place in Japan with measurements only up to 8 hours. Multiple dose trials with the oral formulation administered twice daily showed equipotency or slight superiority over salbutamol4 mg three times daily. Based on the Japanese results, it is suggested that white patients take formoterol, 80 J.Lg twice or three time daily. The early studies with the metered dose aerosol formulation also showed a duration of action of at least 8 hours. For the design of single-dose crossover studies with this long acting compound, one should take into consideration the wash-out period between the examination days. The wash-out period between study

Table 4-Pulae Rate (Beat. per Minute) Formoterol, Hours After Administration Patient No. 01 02 03

04 05 06 07 08 09

10 11

12 13 14 15 16 Mean Std

0*) 88 88 80 68 68 68 68 88 88 84 84 80 80 88 96 88 88 96 88

76 88 80 84

2468 80

88 88 80

72 72

10

12

0*)

88 68 80 68

88 88 68 68

100

92

92

84

84

76 80 76 76 76

76

76 76

84

84 84 84

84 84

76

76

92 84 88 68 96 96 96

88

76 72 72

80 64 64 64 64 64 88 88 88 84 84 84 84 80

76 88 92 92

88 64 80

76 81 89988

76 76 72 88 88 88 88 88 88 80 64

80 92 92

84 80 68 68

76 76 76 76 80

Salbutamol, Hours After Administration

80 84 84 84

76 76 76 80

80

92 92

76 92

72 80

80

76

76

64 84

68 80

79 79 8

72 9

88 80

76 80 64 80 68 68

92

8

12468 84 84 68 64 64 92 96 84

100

104

92

84 80 88 84 92 84 88 84 68 84

92

84 92 80 88

88

92

92

84

92 92

84

76 72 88

88 88 80 84 68 68 68 60

80

76

72

85

83

10

10

80 68

76 68

82 82 11

84 84 80 64 96 84 84 92 88

76 92 80 80 92

80 92

92

80 64 80

76 72 72 76 72 81 10 10

12

88 80

88 84

68 68 64 64

84 88 80

92

10

96 96 80 80 80 80

92 88 80

76 76 80 64 64 64 80 80 80

72

60

80

99

80

76 80

76

96 80 80

76 79 10

*Before administration of trial medication. CHEST I 97 I 3 I MARCH, 1990

593

appeared that about 60 percent of the drug was absorbed from the digestive tract and serum peak levels were measured after 1.5 to 2.0 hours. At the end of each examination day, an additional reversibility test with 2QO J.Lg salbutamol metered dose aerosol was performed. In both groups, the results appeared to be compatible with those obtained on the selection day in respect to maximum bronchodilator effect 15 minutes after administration. This might be an indication that despite the "rest effect" of formoterol 12 hours after administration, no desensitization on the receptor site occurred. The mechanism of action, however, especially on the receptor site, of this inhaled long acting betas-agonist is not yet clear; further studies are therefore recommended. The results of this study on the efficacy and tolerability of 12 J.Lg formoterol metered-dose aerosol in comparison with 200 J.Lg salbutamol confirm the experience of previous investigators2•3 in their conclusions a 12 J.Lg dose of formoterol being both clinically very efficacious and safe in patients with stable and reversible asthma. The bronchospasmolytic capacity and duration of the effect after inhalation of formoterol in this study were quite compatible with earlier investigations; the maximum bronchodilator effect (40 percent above baseline) was reached in 1 to 2 hours, which lasted until6 hours after administration, whereafter a gradual decrease could be observed, leading to still a mean improvement of20 percent above baseline 12 hours after administration. This "rest effect" of 20

584

percent was considered to be clinically relevant and was also statistically significantly better than 200 J.Lg salbutamol, a dosage which is considered worldwide to be therapeutic and safe. Beside this, the bronchospasmolytic effect of formoterol was statistically significantly better than salbutamol from 2 hours onward after administration. The significantly higher therapeutic "rest-effect" 12 hours after administration of formoterol brings new of patients with a soperspectives for the ~reatment called "morning dip" in their lung function, whjch cannot be prevented by the oral or inhaled be~agonists at present on the market {salbutamol, fenoterol, terbutalin, etc). For this reason, further bJ.vestigations with formoterol administered at 22:00 hours followed by nightly registrations of lung function parameters over 12 hours are recommended. REFERENCES

1 Burghele A. Kurzcharakteristik des neuen Beta2-sympathikomimetikums Formoterol. Atemwegs-Lupgenkrankh 1988; 2(suppl):98-100 2 Geisler LS. Bronchodilatierende Wirkung von Fbrmoterol in drei unterschiedlichen Dosierungen per inhalationem. AtemwegsLungenkrankh 1988; 2(suppl):101-()4 3 Nolte D, Meyer pW, Ergebnisse einer Dosisfindungsstudie mit Atemwegs-Lungenkrankh 1988; Formoterol als Dosie~Aerosol. 2(suppl):105-07 4 Loefdahl G, Svedmyr N. Inhaled formoterol: a new beta2adrenoceptor, compared to salbu~ol in asthmatic patients: duration of effect and side effects. Am Rev ~ir Dis 1988; 137:330

lnhP!d Fonnolerol

VB Sallutamol

(M-.n et al)