Eur Resplr J 1988, 1, 223- 226

Comparison between a new once-daily, bronchodilating drug, bambuterol, and terbutaline sustained-release, twice daily

G. Persson*, Y. Gnosspelius**, S. Anehus••

Comparison between a new once-daily , bronchodilating drug, bambutero/, *Department of Internal Medicine, Division of and terburaline sustained-release. twice daily. G. Persson, Y. Gnosspelius. Allergy, University Hospital of Lund. Lu nd, S. Anehus. Sweden. ABSTRACT: Bambuterol is a prodrug, from which terbutaline is slowly **Department of Clinical Research, AB Draco generated. The objectives of the study were to evaluate whether bambuterol, (subsidiary of AB Astra), Lund, Sweden. given once dnily, can control symptoms in asthmatic patients and to compare Correspondence: G. Persson, M.D., Depart­ the bronchodilatmg effect and the side effects with those of terbutaline ment of Internal Medicine, Division of Allergy, sustained-release (SR) tablets given twice daily. Twenty-five out-patients with University Hospital of Lund, S-221 85 LUND, bronchial asthma were treated during two consecutive 14-day periods with Sweden. either 30 mg bambutcrol tabl ets once el·cry el'cning or 2 x 5 mg terbutaline S R tablets morning and evening. The study had a double-blind, cross-over and Keywords: Asthma; bambuterol; prodrug; tcr· randomized design. The mean evening peak expiratory flow rate (PJ.:t

Bambuterol is a new bronchodilator prodrug in the The aim of the present study was to evaluate form of bisdimethy!-carbamate of terbutaline (I]. The whether bambuterol is suitable for once daily admin­ terbutaline part of this prodrug is protected from istration in asthmatic patients, with regard to the being metabolized during absorption and during the duration of its bronchodilating effect and its side first-pass through the liver. This means that bambu­ effects, compared to terbutaline SR treatment twice terol can act as an inner depot from which terbutaline daily. is slowJy generated. Human pharmacological and clinical studies have shown that bambuterol provides Patients and methods safe and reliable generation of terbutaline (2, 3). Sustained-release (SR) terbutaline (administered Twenty-five outpatients (eleven males and fourteen twice daily) has a good bronchodilating effect [4, 5}. females) with bronchial asthma participated in the The bronchodilation obtained is. comparable to that study. AU patients received written and verbal of oral sustained-release preparations of theophylline information and gave their informed consent to [6]. participation. The study was approved by the local Tn the first clinical studies, bambuterol was admin­ Ethics Committee at the University of Lund. istered twice daily [2, 3}. When compared to terbutal­ The study consisted of two consecutive treatment ine SR, the generated terbutaline plasma concentra­ periods, each lasting for fourteen days: bambuterol tion curve and bronchodilation showed a more tablets 30 mg once every evening and terbutaline SR prolonged profile after bambuterol (2]. A good 10 mg (two 5 mg tablets) b.i.d. The treatments were correlation was found between the plasma concentra­ given by using a randomized, double-blind, cross­ tion of terbutaline and the bronchodilating effect. over design with a double-dummy technique. Each Bambuterol given once daily to healthy volunteers patient's medication was provided in blister-packs, in produced a plasma profile of generated terbutaline order to obtain maximal patient compliance. from bambuterol with a peak/trough ratio of I .9 The patients were between 18 and 60 yr old (mean compared to a ratio of 2.4 for terbutaline SR given 40.6 yr) with a mean weight of72.3 kg (range 54 to 95 twice daily (Nyberg et at. , personal communication). kg). The mean d uration of asthma was 21 yr (range These results indicate that bambuterol administered J-45 yr) a nd the mean basal forced expiratory volume only once daily may have a good bronchodilating in o ne second (FEY 1) 2. 18 I (range 0.75- 3.95 !). The effect. mean increase in FEV1 was 44% (19-147%) 15 min 224 G. PERSSON, Y. GNOSSPELJUS, S. ANEHUS

after the last inhalations of terbutaline (Bricanylcorticosteroids were allowed to 130 bambute~:ol continue this treatment, provided that the dosage was 30 1119 x I 120 kept constant during the study. Theophyllines, anti­ · terbut411ne SR cholinergics and other ~-adrenoceptor agonists were 10 1119 • 2 110 ···...... · discontinued, but rimiterol (Pulmadil®) aerosol was ._... · permitted, if needed, but not later than four hours 400 before each PEFR recording. 390 The PEFR was recorded (highest of three values) 380 .__.._.._.__.__...._...._...._...._;_...._;_;_J-.j on the morning and evening before drug intake, using 0 I 2 3 1 5 6 7 8 9 10 II 12 13 14 a Wright mini-Peak Flow Meter. The patients also DAYS recorded their asthma symptoms throughout the day and night (breathlessness, cough, wheezing), the number of times they woke during the night because 150 PEFR £V£:NING of asthma, the use of rimiterol aerosol and the side L/Din. effects (tremor, palpitations, headache and uneasi­ ness) during the day and night. Asthma symptoms 440 and side effects were scored using a six-graded scale: 430 0 =no symptoms; I =slight; 2 =slight to moderate; bambut.erol 30 109 X I 3 =moderate; 4 =moderately severe; 5 =severe symp­ 120 ...... ···,····.• . ••• .~· 0 • • •• ••• toms. ··...... ·· ., ....: .... terbutaline SR HO At the end of the study, the patients were asked in 10 tDq ¥ 2 which of the two periods they experienced the fewest ·.. :" asthmatic symptoms and the fewest side effects and 400 which of the two periods they preferred. 3 90 .__.._.__.__.__".._ .._...._...._1.-1.-.1-.1-.&-.J The statisticaJ evaluations were based on the last 0 I 2 3 4 5 6 7 B 9 10 II 12 13 14 ten days in each 14-day period. A steady state had DAYS then been obtained and the risk of any carry-over Fig. I. Day-to-day variations in the morning PEFR (upper panel) effect was considered to be eliminated. The student's and the evening PEFR (lower panel) during 14 days of treatment paired t-test was used to compare the PEFR and the with bambuterol once daily or sustained-release terbutaline twice daily. Statistical calculations were made on days 5- 14. number of rirniterol puffs in the two periods. The Wilcoxon signed rank test was used in the evaluation of the subjective grading of asthmatic symptoms, the tendency towards fewer asthma symptoms during side effects, the number of times the patients awoke, treatment with bambuterol. Five patients reported and the patient's preference for one of the prepar­ sleep disturbances due to asthma during the bambu­ ations. In this study, the power of the statistical terol period and seven during treatment with terbutal­ evaluation was 80%, using the paired two-tailed t-test ine SR (table I). and a p-value of less than 0.05 to reveal a true Very few patients experienced any side effects and difference of at least 10% in the mean PEFR between those who did scored them as mild-to-moderate (table treatments. 1). There was no difference between the two treatment periods. Fifteen, out of 25 patients, preferred the period Results with bambuterol and only one patient failed to The mean morning PEFR ( ± SEM) was almost the distinguish between the two periods (table 2). same during the two treatments (bambuterol: 425 23 //min; terbutaline: 415 22 1/min), but the ± ± Discussion mean evening PEFR was significantly higher (p

Table 1. -Asthma symptom score, sleep disturbances, side effect score and number of B-aerosol puffs during the last ten days in each period (mean values, n=25)

DAY NIGHT

bambuterol terbutalinc SR bambutcrol tcrbulaline SR

30 mgxl 10 mgx2 30 mgxl 10 mgx2

Asthma symptoms* 0.24 (13) 0.36 (13) 0.11 (9) 0.16 (10)

No. of awakenings 0.04 (5) 0.08 (7)

Tremor* 0.06 (3) 0.10 (4) 0 (0) 0.02 (1)

Palpitations* O.Ql (1) 0.02 (3) 0 (0) 0 (0)

Headache* O.Q7 (6) 0.05 (5) 0.04 (4) 0.06 (7)

Uneasiness* 0 (0) 0.01 (1) 0 (0) O.o2 (2)

Mean no. of puffs 0.70±0.29 1.04±0.39 0.18±0.08 0.32±0.16

p<0.05

* Score using a six-grade scale (0--5). Number of patients reporting asthma symptoms, sleep disturbances and/or any side effect is in brackets.

Table 2. -Preferences for the two treatments (number of the morning. This probably reflects the slow absorp­ patients, n=25) tion of terbutaline from terbutaline SR during the night, compared with the day, resulting in a high bambuterol terbutaline SR no preference plasma concentration of terbutaline in the morning 30mgx1 10 mgx2 and consequently a good morning lung function. Thus, the present study is in accordance with the Fewest side results in healthy volunteers where bambuterol given effects 12 7 6 once daily produced a more prolonged and stable terbutaline plasma concentration curve than did Fewest asthma terbutaline SR (b.i.d.). (NYBERG et a/., personal symptoms 15 6 4 communication). In contrast to the present study, the results of Preference 15 9 1 another study in asthmatic patients revealed that treatment with bambuterol given once daily produced the same bronchodilation and the same incidence of regimen. Terbutaline SR has been shown to have a side effects as did terbutaline SR given twice daily [9]. more prolonged duration of effect than plain tablets The doses and dosage regimens used were the same as [7] and it can prevent early morning dyspnoea [8]. those in the present study. However, the patients were Compared to plain terbutaline tablets, treatment with somewhat older and had a lower mean basal FEV 1 terbutaline SR tablets increases the morning lung value than those in the present study. They also used function values in asthmatic patients [4, 5]. more ~-adrenoceptor agonist aerosol during both The administration of bambuterol once daily to treatments. About two-thirds of the patients were also asthmatic patients produced better bronchodilation dependent on corticosteroid treatment, as compared and fewer asthma symptoms than terbutaline SR to about one-third in tbe present study. These given twice daily. The PEFR, recorded in the evening differences may have contributed to the discrepancy (24 h after administration of bambuterol and 12 h in results between the two studies. after the morning dose of terbutaline SR), was In conclusion, bambuterol seems to be suitable for significantly higher during bambuterol treatment, a once daily administration to asthmatic patients. which indicates a clinically significantly prolonged When administered once daily, 30 mg bambuterol duration of effect without any increase in the provides better bronchodilation, with the same fre­ frequency and intensity of side effects. No significant quency and intensity of side effects, than does 10 mg difference in PEFR was seen between the two drugs in terbutaline SR given twice daily. 226 G. PERSSON, Y. GNOSSPELIUS, S. ANEHUS

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