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Clickhaler (a Novel Dry Powder Inhaler) Provides Similar Bronchodilation to Pressurized Metered-Dose Inhaler, Even at Low Flow Rates
Clickhaler (a Novel Dry Powder Inhaler) Provides Similar Bronchodilation to Pressurized Metered-Dose Inhaler, Even at Low Flow Rates* Michael T. Newhouse, MD, FCCP; Normand P. Nantel, PhD; Carole B. Chambers, AHT; Barbara Pratt, RN; and Mark Parry-Billings, DPhil
Study objective: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma. Design: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 mg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol. Active (albuterol via pMDI inhaled at 30 L/min) and placebo controls were included. Setting: Single center study at the chest/allergy unit of a teaching hospital in Canada. Patients: Sixteen patients with moderate to moderately severe stable asthma. Measurements and results: Efficacy end points were FEV1, FVC, FEV1/FVC, maximum expiratory flow, and forced expiratory flow between 25% and 75% of vital capacity. Safety end points included heart rate, BP, and tremor. There was no significant difference between the bronchodilator response to albuterol via the CH at 15, 30, and 60 L/min inspiratory flow rate and, at all flow rates, no significant difference was found comparing albuterol CH with the pMDI. All of the techniques for delivering albuterol provided significantly better bronchodilatation than placebo. Adverse events were minimal and did not differ between CH and pMDI or between the various flow rates inhaled through the CH. Conclusion: A novel passive albuterol DPI (CH) provides a similar bronchodilator response at 15, 30, and 60 L/min inspiratory flow rates compared with a pMDI used optimally. (CHEST 1999; 115:952–956) Key words: albuterol; bronchodilatation; dry powder inhaler; inspiratory flow rate Abbreviations: CH 5 Clickhaler; DPI 5 dry powder inhaler; FEF25–75 5 forced expired flow between 25% and 75% of vital capacity; MDI 5 metered-dose inhaler; MEF 5 maximum expiratory flow; pMDI 5 pressurized metered-dose inhaler
lbuterol is a potent, selective b -agonist with a A rapid onset of action. It is widely used for the 2
treatment and prophylaxis of bronchospasm in asthma and other conditions associated with reversible airflow obstruction. The most popular method of administration of the drug for these conditions has
*From the Barnett Medical Aerosol Research Laboratory (Drs. Newhouse and Nantel and Mss Chambers and Pratt), St. Joseph’s Hospital-McMaster University, Hamilton, Ontario, Canada, and ML Laboratories PLC (Dr. Parry-Billings), St. Albans, Hertfordshire, UK. This research was sponsored by ML Laboratories PLC, St. Albans, UK. Manuscript received March 10, 1998; revision accepted September 4, 1998. Correspondence to: M. Newhouse, MD, FCCP, Inhale Therapeutic Systems, 150 Industrial Road, San Carlos, CA 94070; e-mail: [email protected] 952
been via a pressurized metered-dose inhaler (pMDI), a robust and simple device that has been in use for 40 years. Recently, the development of new dry powder inhalers (DPIs) was triggered by the potential phase-out of the chlorofluorocarbon propellants used in pMDIs.1 There are other advantages to DPIs; for example, the patient’s inspiratory effort ensures aerosolization of drug with inhalation, whereas with pMDIs, suboptimal actuation-inhalation coordination can result in decreased drug delivery to the lungs.2 All currently available (so-called “passive”) DPIs require the patient’s vigorous inspiratory effort to both disperse and deliver the powder formulation. It has also been shown that, when using a passive DPI, inspiratory flow rate is correlated with drug deposiClinical Investigations
tion,3,4 with low inspiratory flow rates leading to reduced lower respiratory tract fine particle drug delivery and therapeutic response.5 The Clickhaler (CH) (ML Laboratories PLC; St. Albans, UK) is a novel passive DPI; therefore, it was considered important to evaluate the bronchodilator efficacy of the albuterol sulfate CH over a range of inspiratory flow rates, particularly the low inspiratory flow rates that might be encountered under conditions of severe airflow obstruction common to severe exacerbations of asthma or COPD and in children , 6 years.6 The study was designed to compare the bronchodilator response of a novel DPI (CH) at inspiratory flow rates of 15, 30, and 60 L/min with albuterol pMDI used optimally and placebo in patients with asthma.
Materials and Methods Subjects Sixteen patients with moderate to moderately severe asthma were enrolled over a 12-month period. For inclusion in the study, patients had a diagnosis of asthma according to the guidelines of the National Heart, Lung, and Blood Institute,7 were $ 18 years of age and nonsmokers, or asthmatics with , 10 pack-years of smoking history who had not smoked for at least 15 years. Patients had a resting FEV1 of 40 to 80% of predicted normal and a minimum 15% increase of FEV1 to 200 mg of albuterol inhaled under the supervision of the study coordinator, using a pMDI (Ventolin; Allen & Hanburys; Uxbridge, UK) with the closed mouth method. Over the course of the study, patients continued their use of steroids, cromolyn sodium, or nedocromil sodium for asthma control. Prior to each study visit, use of asthma medication, caffeine, and alcohol was discontinued for at least 8 h. Patients with concomitant respiratory diseases such as cystic fibrosis, tuberculosis, or COPD were excluded from the study. The protocol was approved by the Institutional Review Board of St. Joseph’s Hospital, Hamilton, Ontario, and by Health and Welfare, Canada (Health Protection Branch). Written informed consent was obtained from all patients. Study Design This was a single-center, randomized, double-blind, five-way crossover study, that compared the effects of albuterol CH at inspiratory flow rates of 15, 30, and 60 L/min, with an albuterol pMDI used with lips closed about the mouthpiece at a monitored inspiratory flow rate of 30 L/min and a placebo inhalation (pMDI at 30 L/min). The study involved a screening visit and five randomized treatment visits. Inspiratory flows through the CH (Fig 1) were determined by measuring the pressure at the mouthpiece using a small unobtrusive sampling tube leading to a pressure transducer.8 The resistance of the DPI had been calculated previously from its characteristic pressure-flow curve. Inspiratory flows through the metered-dose inhaler (MDI) were recorded with a pneumotachometer and displayed on an oscilloscope and chart recorder. The pneumotachometer was connected to the MDI boot by a
Figure 1. The CH, a novel multidose DPI (US patent 5,437,720). The CH is a reservoir device that delivers 200 doses. When the patient presses or “clicks” the button on the top of the device, a metering cone carries a single dose from the drug hopper into the inhalation passage. The patient then breathes out normally, closes the lips around the mouthpiece, and inhales. The device has a number of safety features, including a dose counter on the back and a “lock-out” after 200 doses. As only one metered dose can be present in the inhalation passage at one time, double dosing is prevented.
plastic bulb approximately 7 cm in diameter and sealed around both end fittings. To allow MDI actuation, a hole was made into the side of the bulb and fitted with a sealed finger cot. A laboratory-grade electronic manometer was employed to calibrate both sensors to within an error of 0.05 cm H2O. The nominal dose of albuterol in all cases was 200 mg (2 3 100 mg). At each visit, the patient inhaled twice from a pMDI and twice each from three CHs, at the flow rates given earlier. For the placebo arm of the treatment, all four inhalers were placebo. For the active arms of the treatment, one of the inhalers contained albuterol and the other three were placebo. Study Assessments At the screening visit, a flow volume loop was obtained using a spirometer (Compact; Vitalograph Ltd; Buckingham, UK) before drug administration to provide the FEV1, maximum expiratory flow (MEF), FVC, forced expired flow between 25% and 75% of vital capacity (FEF25–75) and FEV1/FVC ratio. At the screening visit, FEV1 was also measured postalbuterol via pMDI. At each treatment visit, spirometry was performed pretreatment and at 15, 30, 45, 60, 90, 120, 180, and 240 min posttreatment. At each study visit, the baseline FEV1 was within 615% of that obtained at the screening visit. Safety Assessments BP, heart rate (by three-lead ECG rhythm strip), tremor,9 and respiratory rate were recorded at each visit, before treatment and at 30, 60, 120, and 240 min posttreatment. All adverse events occurring throughout the study period were also recorded. CHEST / 115 / 4 / APRIL, 1999
953
Inspiratory Flow Rate Targeting and Monitoring Following appropriate training, patients were able to provide mean peak inspiratory flow rates (625%) of 15, 30, and 60 L/min. The inspiratory flows were measured and displayed in real time using a computerized DPI flow targeting system (Clinical Flow Technologies; Hamilton, Ontario, Canada).8 During inhalation, the instrument measured mouth pressure via a small, unobtrusive tube at the CH mouthpiece. Using the predetermined resistance of the CH, pressure measurement values were converted to flow values. Patients observed their inspiratory flows in real-time on a computer monitor and, after appropriate training, were thus able to adjust their efforts to provide inspiratory flow rates within the target range. Data Analysis Data are presented as mean 6 SD unless otherwise indicated. All analyses were compared between treatment groups by analysis of variance. The primary efficacy analysis was the magnitude of the change in FEV1. Secondary efficacy analyses were also performed on measurements of MEF, FEF25–75, FVC, and the ratio of FEV1/ FVC. The duration of the response was investigated using the area under the FEV1 response vs time curve between 0 and 240 min posttreatment. Differences were considered significant at the 5% level. Safety analyses involved comparison of the mean changes in heart rate, BP, respiratory rate, and tremor between the treatment groups, compared with baseline pretreatment and placebo response over time.
cantly different from placebo (Fig 2; p , 0.05). There were no significant differences among the four albuterol treatments (p 5 0.68, analysis of variance excluding placebo arm). There was an overall significant treatment effect in the duration of the FEV1 response (p , 0.0001), but this was not significant among the four albuterol treatments. There were no significant differences among the active treatments for these parameters (Table 2). The changes from baseline in FVC, MEF, FEF25–75, and FEV1/FVC ratio (Fig 3) following the four albuterol treatments were significantly greater than those observed for placebo (p , 0.05). For all these indexes of lung function, there were no significant differences among the active treatments. Adverse Events There were no remarkable adverse events reported. Of a total of nine adverse events, only one of these (mild sore throat and hoarseness) was reported as being possibly related to the CH. Vital Signs and Tremor There were no clinically significant changes in systolic/diastolic BP, heart rate, respiratory rate, or tremor following any of the study treatments.
Results All sixteen patients completed the six study visits. The demographics and vital signs of the patients at entry are shown in Table 1. Lung Function Variables The changes in FEV1 over time from baseline following the four albuterol treatments were signifi-
Discussion A major limitation of passive DPIs is their potential for reduced fine particle output owing to inadequate powder deaggregation at flow rates , 60 L/min.10
Table 1—Patient Demographics and Vital Signs at Entry to the Study* Characteristic Sex, No. Male Female Age, yr Height, cm Weight, kg Baseline FEV1 % of predicted value Volume, L Reversibility to albuterol (increase in FEV1), % Volume, L BP, mm Hg Systolic Diastolic Heart rate, beats/min Respiratory rate, breaths/min *All values are mean 6 SD (range). 954
Value 12 4 57.3 6 18.0 (22–76) 176 6 9 (161–188) 77.7 6 11.6 (61–106) 60 6 9 (46–78) 2.09 6 0.75 (1.04–3.68) 25.0 6 9.33 (16–49) 0.49 6 0.15 (0.26–0.69) 119 6 13 (98–150) 71 6 12 (54–98) 72 6 10 (52–92) 17 6 3 (12–22)
Figure 2. Change from baseline in FEV1 following albuterol or placebo. Changes from baseline in FEV1 were measured following administration of albuterol via CH at 15, 30, or 60 L/min, or pMDI at 30 L/min, or placebo. The changes from baseline following the four albuterol treatments were significantly greater than those observed after placebo (p , 0.05). There were no significant differences among the four albuterol treatments. Clinical Investigations
Table 2—Maximum Change in FEV1 and Time to Maximum Response Following Administration of Albuterol via the DPI and pMDI and Placebo
Treatment
Maximum Change in FEV1 From Baseline, L*
Time to Maximum, min*
DPI, 15 L/min DPI, 30 L/min DPI, 60 L/min pMDI, 30 L/min Placebo
0.44 6 0.16 0.45 6 0.19 0.53 6 0.24 0.46 6 0.18 0.19 6 0.13
85.3 6 37.4 97.5 6 59.5 81.6 6 56.1 88.1 6 43.8 129.4 6 88.8
*Mean 6 SD.
Previous in vitro work to characterize the aerosol output from the CH has demonstrated that both the emitted dose and the particle size distribution of the emitted dose are relatively constant over the range of flow rates used in the present study.11 To our
knowledge, the correlation between these in vitro measurements and in vivo measures of clinical efficacy, however, has not been studied previously with this device. In the present study, no significant differences were found in bronchodilator response between the CH over the clinically relevant range of flow rates studied (15 to 60 L/min) and the pMDI inhaled under near-optimum conditions. This finding was consistent for all spirometric parameters and for the duration of the response. Studies have confirmed that most patients are able to achieve an inspiratory flow rate of at least 30 L/min through the CH. In pediatric patients with asthma (mean age, 12.9 years; range, 7 to 14 years), the mean peak inspiratory flow rate through the CH was 74.4 L/min and the lowest was 62.1 L/min.12 In the present study, all patients were able to achieve the flow rates required. Therefore, the range of flow
Figure 3. Change from baseline in MEF, FVC, FEF25–75, and FEV1/FVC following albuterol or placebo. Changes from baseline in MEF, FVC, FEF25–75, and FEV1/FVC were measured following administration of albuterol via CH at 15, 30, or 60 L/min, or pMDI at 30 L/min, or placebo. The changes from baseline following the four albuterol treatments were significantly greater than those observed for placebo (p , 0.01). There were no significant differences among the four albuterol treatments. CHEST / 115 / 4 / APRIL, 1999
955
rates evaluated represents those that are actually achieved by children . 6 years and adults with asthma in routine clinical practice. Furthermore, the finding in this study of the clinical equivalence of albuterol pMDI and CH in asthmatics confirms the results of a previous study in 62 patients with reversible airflow obstruction.13 Another study with the albuterol CH used a pharmacokinetic method.14 Urinary excretion of albuterol and metabolites at 30 min and 24 h was measured as an indication of the relative lung deposition and total body bioavailability of albuterol, respectively, and showed that the relative lung bioavailability delivered via the CH was similar at relatively slow and fast inspiratory flow rates (30.1 6 0.91 L/min and 58.9 6 2.6 L/min, respectively).15 Further studies measuring lung deposition using gamma scintigraphy have demonstrated that there is no correlation between inspiratory flow rate and lung deposition.16 Conclusion The clinical efficacy and safety of the CH, which are similar to those of the Ventolin pMDI used in an optimal fashion, are independent of inspiratory flow rate in the clinically relevant range of 15 to 60 L/min in children . 6 years and adults. ACKNOWLEDGMENTS: The authors would like to thank Alison Scrimgeour, who performed the statistical analysis of the study, and Dr. C. E. Birrell, for assistance with the manuscript.
References 1 Newhouse MT. Pulmonary drug targeting with aerosols: principles and clinical applications in adults and children. Am J Asthma Allergy Pediatr 1993; 7:23–35 2 Newman SP, Clarke SW. Aerosols in therapy. In: Moren F, Newhouse MT, Dolovich MB, eds. Aerosols in medicine: principles, diagnosis and therapy. New York, NY: Elsevier, 1985; 289 –312 3 Richards R, Simpson SF, Renwick AG, et al. Inhalation rate of sodium cromoglycate determines plasma pharmacokinetics and protection against AMP-induced bronchoconstriction in
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asthma. Eur Respir J 1988; 1:896 –901 4 Engel T, Scharling B, Skovsted B, et al. Effects, side effects and plasma concentrations of terbutaline in adult asthmatics after inhaling from a dry powder inhaler device at different inhalation flows and volumes. Br J Clin Pharmacol 1992; 33:439–444 5 Olsson B, Asking L, Borgstro¨m L, et al. Effect of inlet throat on the correlation between fine particle dose and lung deposition. In: Dalby RN, Byron PR, Farr ST, eds. Respiratory drug delivery (vol 5). Buffalo Grove, IL: Interpharm Inc, 1996; 273–281 6 Pedersen S, Hansen OR, Fuglsang G. Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch Dis Child 1990; 65:308 –319 7 National Heart, Lung, and Blood Institute. Guidelines on the diagnosis and treatment of asthma. Pediatr Asthma Allergy Immunol 1991; 5:57–72 8 Nantel NP, Smerek JC, Newhouse MT. Flow targeting system for DPI clinical trials [abstract]. J Aerosols Med 1995; 8:A103 9 Thiringer G, Svedmyr N. Evaluation of skeletal muscle tremor due to bronchodilator agents. Scand J Respir Dis 1975; 56:93–102 10 Newman SP, More´n FD, Trufust E, et al. Terbutaline sulphate Turbuhaler: effect of inhaled flow rate on drug deposition and efficacy. Int J Pharm 1991; 74:209 –213 11 Barrowcliffe J, McGlynn P, Tickle S, et al. The in-vitro evaluation of a novel multi-dose dry powder inhaler. In: Drug delivery to the lungs (vol 7). Bristol, UK: Aerosol Society, 1996; 82– 85 12 Nantel NP, Newhouse MT, Sears MR. Pediatric inspiratory flows through a novel multidose DPI. In: Dalby RN, Byron PR, Farr ST, eds. Respiratory drug delivery (vol 5). Buffalo Grove, IL: Interpharm Inc, 1996; 386 –388 13 Morice AH, Peake MD, Allen MB, et al. Comparison of the efficacy and safety of salbutamol delivered via a novel multidose dry powder inhaler (DPI) or a metered dose inhaler (MDI) before and after a period of clinical use [abstract]. Eur Respir J 1996; 9:S23 14 Hindle M, Chrystyn H. Determination of the relative bioavailability of salbutamol to the lung following inhalation. Br J Clin Pharmacol 1992; 34:311–315 15 Chege JK, Chrystyn H. Salbutamol lung deposition is dependent on inhalation rate and formulation [abstract]. J Pharm Pharmacol 1995; 47:1098 16 Warren SJ, Taylor G. Effect of inhalation flow profiles on the deposition of radiolabeled BDP from a novel dry powder inhaler (DPI, Clickhaler), a conventional metered dose inhaler (MDI) and MDI plus spacer. In: Dalby RN, Byron PR, Farr ST, eds. Respiratory drug delivery (vol 6). Buffalo Grove, IL: Interpharm Inc, 1998; 453– 455
Clinical Investigations
Study objective: Comparison of the bronchodilator response to an albuterol novel dry powder inhaler (DPI) (Clickhaler [CH]; ML Laboratories PLC; St. Albans, UK) activated at various inspiratory flow rates and to an albuterol pressurized metered-dose inhaler (pMDI) by patients with moderate to moderately severe stable asthma. Design: Randomized, double-blind, placebo-controlled comparison of the bronchodilator response to albuterol DPI (200 mg) at inspiratory flow rates of approximately 15, 30, and 60 L/min in patients with stable asthma with demonstrated reversibility to albuterol. Active (albuterol via pMDI inhaled at 30 L/min) and placebo controls were included. Setting: Single center study at the chest/allergy unit of a teaching hospital in Canada. Patients: Sixteen patients with moderate to moderately severe stable asthma. Measurements and results: Efficacy end points were FEV1, FVC, FEV1/FVC, maximum expiratory flow, and forced expiratory flow between 25% and 75% of vital capacity. Safety end points included heart rate, BP, and tremor. There was no significant difference between the bronchodilator response to albuterol via the CH at 15, 30, and 60 L/min inspiratory flow rate and, at all flow rates, no significant difference was found comparing albuterol CH with the pMDI. All of the techniques for delivering albuterol provided significantly better bronchodilatation than placebo. Adverse events were minimal and did not differ between CH and pMDI or between the various flow rates inhaled through the CH. Conclusion: A novel passive albuterol DPI (CH) provides a similar bronchodilator response at 15, 30, and 60 L/min inspiratory flow rates compared with a pMDI used optimally. (CHEST 1999; 115:952–956) Key words: albuterol; bronchodilatation; dry powder inhaler; inspiratory flow rate Abbreviations: CH 5 Clickhaler; DPI 5 dry powder inhaler; FEF25–75 5 forced expired flow between 25% and 75% of vital capacity; MDI 5 metered-dose inhaler; MEF 5 maximum expiratory flow; pMDI 5 pressurized metered-dose inhaler
lbuterol is a potent, selective b -agonist with a A rapid onset of action. It is widely used for the 2
treatment and prophylaxis of bronchospasm in asthma and other conditions associated with reversible airflow obstruction. The most popular method of administration of the drug for these conditions has
*From the Barnett Medical Aerosol Research Laboratory (Drs. Newhouse and Nantel and Mss Chambers and Pratt), St. Joseph’s Hospital-McMaster University, Hamilton, Ontario, Canada, and ML Laboratories PLC (Dr. Parry-Billings), St. Albans, Hertfordshire, UK. This research was sponsored by ML Laboratories PLC, St. Albans, UK. Manuscript received March 10, 1998; revision accepted September 4, 1998. Correspondence to: M. Newhouse, MD, FCCP, Inhale Therapeutic Systems, 150 Industrial Road, San Carlos, CA 94070; e-mail: [email protected] 952
been via a pressurized metered-dose inhaler (pMDI), a robust and simple device that has been in use for 40 years. Recently, the development of new dry powder inhalers (DPIs) was triggered by the potential phase-out of the chlorofluorocarbon propellants used in pMDIs.1 There are other advantages to DPIs; for example, the patient’s inspiratory effort ensures aerosolization of drug with inhalation, whereas with pMDIs, suboptimal actuation-inhalation coordination can result in decreased drug delivery to the lungs.2 All currently available (so-called “passive”) DPIs require the patient’s vigorous inspiratory effort to both disperse and deliver the powder formulation. It has also been shown that, when using a passive DPI, inspiratory flow rate is correlated with drug deposiClinical Investigations
tion,3,4 with low inspiratory flow rates leading to reduced lower respiratory tract fine particle drug delivery and therapeutic response.5 The Clickhaler (CH) (ML Laboratories PLC; St. Albans, UK) is a novel passive DPI; therefore, it was considered important to evaluate the bronchodilator efficacy of the albuterol sulfate CH over a range of inspiratory flow rates, particularly the low inspiratory flow rates that might be encountered under conditions of severe airflow obstruction common to severe exacerbations of asthma or COPD and in children , 6 years.6 The study was designed to compare the bronchodilator response of a novel DPI (CH) at inspiratory flow rates of 15, 30, and 60 L/min with albuterol pMDI used optimally and placebo in patients with asthma.
Materials and Methods Subjects Sixteen patients with moderate to moderately severe asthma were enrolled over a 12-month period. For inclusion in the study, patients had a diagnosis of asthma according to the guidelines of the National Heart, Lung, and Blood Institute,7 were $ 18 years of age and nonsmokers, or asthmatics with , 10 pack-years of smoking history who had not smoked for at least 15 years. Patients had a resting FEV1 of 40 to 80% of predicted normal and a minimum 15% increase of FEV1 to 200 mg of albuterol inhaled under the supervision of the study coordinator, using a pMDI (Ventolin; Allen & Hanburys; Uxbridge, UK) with the closed mouth method. Over the course of the study, patients continued their use of steroids, cromolyn sodium, or nedocromil sodium for asthma control. Prior to each study visit, use of asthma medication, caffeine, and alcohol was discontinued for at least 8 h. Patients with concomitant respiratory diseases such as cystic fibrosis, tuberculosis, or COPD were excluded from the study. The protocol was approved by the Institutional Review Board of St. Joseph’s Hospital, Hamilton, Ontario, and by Health and Welfare, Canada (Health Protection Branch). Written informed consent was obtained from all patients. Study Design This was a single-center, randomized, double-blind, five-way crossover study, that compared the effects of albuterol CH at inspiratory flow rates of 15, 30, and 60 L/min, with an albuterol pMDI used with lips closed about the mouthpiece at a monitored inspiratory flow rate of 30 L/min and a placebo inhalation (pMDI at 30 L/min). The study involved a screening visit and five randomized treatment visits. Inspiratory flows through the CH (Fig 1) were determined by measuring the pressure at the mouthpiece using a small unobtrusive sampling tube leading to a pressure transducer.8 The resistance of the DPI had been calculated previously from its characteristic pressure-flow curve. Inspiratory flows through the metered-dose inhaler (MDI) were recorded with a pneumotachometer and displayed on an oscilloscope and chart recorder. The pneumotachometer was connected to the MDI boot by a
Figure 1. The CH, a novel multidose DPI (US patent 5,437,720). The CH is a reservoir device that delivers 200 doses. When the patient presses or “clicks” the button on the top of the device, a metering cone carries a single dose from the drug hopper into the inhalation passage. The patient then breathes out normally, closes the lips around the mouthpiece, and inhales. The device has a number of safety features, including a dose counter on the back and a “lock-out” after 200 doses. As only one metered dose can be present in the inhalation passage at one time, double dosing is prevented.
plastic bulb approximately 7 cm in diameter and sealed around both end fittings. To allow MDI actuation, a hole was made into the side of the bulb and fitted with a sealed finger cot. A laboratory-grade electronic manometer was employed to calibrate both sensors to within an error of 0.05 cm H2O. The nominal dose of albuterol in all cases was 200 mg (2 3 100 mg). At each visit, the patient inhaled twice from a pMDI and twice each from three CHs, at the flow rates given earlier. For the placebo arm of the treatment, all four inhalers were placebo. For the active arms of the treatment, one of the inhalers contained albuterol and the other three were placebo. Study Assessments At the screening visit, a flow volume loop was obtained using a spirometer (Compact; Vitalograph Ltd; Buckingham, UK) before drug administration to provide the FEV1, maximum expiratory flow (MEF), FVC, forced expired flow between 25% and 75% of vital capacity (FEF25–75) and FEV1/FVC ratio. At the screening visit, FEV1 was also measured postalbuterol via pMDI. At each treatment visit, spirometry was performed pretreatment and at 15, 30, 45, 60, 90, 120, 180, and 240 min posttreatment. At each study visit, the baseline FEV1 was within 615% of that obtained at the screening visit. Safety Assessments BP, heart rate (by three-lead ECG rhythm strip), tremor,9 and respiratory rate were recorded at each visit, before treatment and at 30, 60, 120, and 240 min posttreatment. All adverse events occurring throughout the study period were also recorded. CHEST / 115 / 4 / APRIL, 1999
953
Inspiratory Flow Rate Targeting and Monitoring Following appropriate training, patients were able to provide mean peak inspiratory flow rates (625%) of 15, 30, and 60 L/min. The inspiratory flows were measured and displayed in real time using a computerized DPI flow targeting system (Clinical Flow Technologies; Hamilton, Ontario, Canada).8 During inhalation, the instrument measured mouth pressure via a small, unobtrusive tube at the CH mouthpiece. Using the predetermined resistance of the CH, pressure measurement values were converted to flow values. Patients observed their inspiratory flows in real-time on a computer monitor and, after appropriate training, were thus able to adjust their efforts to provide inspiratory flow rates within the target range. Data Analysis Data are presented as mean 6 SD unless otherwise indicated. All analyses were compared between treatment groups by analysis of variance. The primary efficacy analysis was the magnitude of the change in FEV1. Secondary efficacy analyses were also performed on measurements of MEF, FEF25–75, FVC, and the ratio of FEV1/ FVC. The duration of the response was investigated using the area under the FEV1 response vs time curve between 0 and 240 min posttreatment. Differences were considered significant at the 5% level. Safety analyses involved comparison of the mean changes in heart rate, BP, respiratory rate, and tremor between the treatment groups, compared with baseline pretreatment and placebo response over time.
cantly different from placebo (Fig 2; p , 0.05). There were no significant differences among the four albuterol treatments (p 5 0.68, analysis of variance excluding placebo arm). There was an overall significant treatment effect in the duration of the FEV1 response (p , 0.0001), but this was not significant among the four albuterol treatments. There were no significant differences among the active treatments for these parameters (Table 2). The changes from baseline in FVC, MEF, FEF25–75, and FEV1/FVC ratio (Fig 3) following the four albuterol treatments were significantly greater than those observed for placebo (p , 0.05). For all these indexes of lung function, there were no significant differences among the active treatments. Adverse Events There were no remarkable adverse events reported. Of a total of nine adverse events, only one of these (mild sore throat and hoarseness) was reported as being possibly related to the CH. Vital Signs and Tremor There were no clinically significant changes in systolic/diastolic BP, heart rate, respiratory rate, or tremor following any of the study treatments.
Results All sixteen patients completed the six study visits. The demographics and vital signs of the patients at entry are shown in Table 1. Lung Function Variables The changes in FEV1 over time from baseline following the four albuterol treatments were signifi-
Discussion A major limitation of passive DPIs is their potential for reduced fine particle output owing to inadequate powder deaggregation at flow rates , 60 L/min.10
Table 1—Patient Demographics and Vital Signs at Entry to the Study* Characteristic Sex, No. Male Female Age, yr Height, cm Weight, kg Baseline FEV1 % of predicted value Volume, L Reversibility to albuterol (increase in FEV1), % Volume, L BP, mm Hg Systolic Diastolic Heart rate, beats/min Respiratory rate, breaths/min *All values are mean 6 SD (range). 954
Value 12 4 57.3 6 18.0 (22–76) 176 6 9 (161–188) 77.7 6 11.6 (61–106) 60 6 9 (46–78) 2.09 6 0.75 (1.04–3.68) 25.0 6 9.33 (16–49) 0.49 6 0.15 (0.26–0.69) 119 6 13 (98–150) 71 6 12 (54–98) 72 6 10 (52–92) 17 6 3 (12–22)
Figure 2. Change from baseline in FEV1 following albuterol or placebo. Changes from baseline in FEV1 were measured following administration of albuterol via CH at 15, 30, or 60 L/min, or pMDI at 30 L/min, or placebo. The changes from baseline following the four albuterol treatments were significantly greater than those observed after placebo (p , 0.05). There were no significant differences among the four albuterol treatments. Clinical Investigations
Table 2—Maximum Change in FEV1 and Time to Maximum Response Following Administration of Albuterol via the DPI and pMDI and Placebo
Treatment
Maximum Change in FEV1 From Baseline, L*
Time to Maximum, min*
DPI, 15 L/min DPI, 30 L/min DPI, 60 L/min pMDI, 30 L/min Placebo
0.44 6 0.16 0.45 6 0.19 0.53 6 0.24 0.46 6 0.18 0.19 6 0.13
85.3 6 37.4 97.5 6 59.5 81.6 6 56.1 88.1 6 43.8 129.4 6 88.8
*Mean 6 SD.
Previous in vitro work to characterize the aerosol output from the CH has demonstrated that both the emitted dose and the particle size distribution of the emitted dose are relatively constant over the range of flow rates used in the present study.11 To our
knowledge, the correlation between these in vitro measurements and in vivo measures of clinical efficacy, however, has not been studied previously with this device. In the present study, no significant differences were found in bronchodilator response between the CH over the clinically relevant range of flow rates studied (15 to 60 L/min) and the pMDI inhaled under near-optimum conditions. This finding was consistent for all spirometric parameters and for the duration of the response. Studies have confirmed that most patients are able to achieve an inspiratory flow rate of at least 30 L/min through the CH. In pediatric patients with asthma (mean age, 12.9 years; range, 7 to 14 years), the mean peak inspiratory flow rate through the CH was 74.4 L/min and the lowest was 62.1 L/min.12 In the present study, all patients were able to achieve the flow rates required. Therefore, the range of flow
Figure 3. Change from baseline in MEF, FVC, FEF25–75, and FEV1/FVC following albuterol or placebo. Changes from baseline in MEF, FVC, FEF25–75, and FEV1/FVC were measured following administration of albuterol via CH at 15, 30, or 60 L/min, or pMDI at 30 L/min, or placebo. The changes from baseline following the four albuterol treatments were significantly greater than those observed for placebo (p , 0.01). There were no significant differences among the four albuterol treatments. CHEST / 115 / 4 / APRIL, 1999
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rates evaluated represents those that are actually achieved by children . 6 years and adults with asthma in routine clinical practice. Furthermore, the finding in this study of the clinical equivalence of albuterol pMDI and CH in asthmatics confirms the results of a previous study in 62 patients with reversible airflow obstruction.13 Another study with the albuterol CH used a pharmacokinetic method.14 Urinary excretion of albuterol and metabolites at 30 min and 24 h was measured as an indication of the relative lung deposition and total body bioavailability of albuterol, respectively, and showed that the relative lung bioavailability delivered via the CH was similar at relatively slow and fast inspiratory flow rates (30.1 6 0.91 L/min and 58.9 6 2.6 L/min, respectively).15 Further studies measuring lung deposition using gamma scintigraphy have demonstrated that there is no correlation between inspiratory flow rate and lung deposition.16 Conclusion The clinical efficacy and safety of the CH, which are similar to those of the Ventolin pMDI used in an optimal fashion, are independent of inspiratory flow rate in the clinically relevant range of 15 to 60 L/min in children . 6 years and adults. ACKNOWLEDGMENTS: The authors would like to thank Alison Scrimgeour, who performed the statistical analysis of the study, and Dr. C. E. Birrell, for assistance with the manuscript.
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Clinical Investigations