Pearl Therapeutics

Jan 5, 2022

PIF is a potential indicator for effective DPI use; 9 however, the approach for measuring PIF is not standardized. Therefore, an accurate assessment of the prevalence of suboptimal PIF and its impact on clinical outcomes cannot be ascertained. Variables in PIF assessment include the device used for assessment, instructions for exhalation before inhalation (eg, from RV; after forced expiration or slow exhalation vs FRC; after passive end-tidal expiration), number of resistance settings tested, physical position of the patient with the inhaler, and PIF calculation (one measurement vs average of multiple measurements vs best of multiple measurements). Notably, the intensity of inspiratory effort (eg, “sharp,” “quick,” “maximal,” “forceful,” and “full”) differs based on patients’ perceptions and varies for each inhaler according to the respective Instructions for Use. For example, a “sharp, maximal” effort will produce a different PIF versus a “full, deep” breath. Herein, we describe findings from a systematic evaluation of recommended and applied PIF assessment approaches and, accordingly, propose a practical and standardized method of PIF measurement. Methods Consensus Development An international panel of experts was convened under the leadership of J.A.O., D.A.M., G.T.F., and O.S.U. We agreed that a standardized approach to measuring PIF in clinical trials and daily clinical practice was needed and posed the following three questions that needed to be addressed: (1) How should patients and the PIF assessment device be positioned during assessment?, (2) How should patients be instructed to exhale before assessment?, and (3) How should patients be instructed to inhale during assessment? We devised an approach to collect relevant information from published sources (Instructions for Use of In-Check™ DIALs and applicable DPIs, as well as published literature), reviewed the information, and drafted recommendations based on the findings, as well as our clinical and research experience. Consensus on the recommendations was achieved through iterative discussion and review of available literature. In-Check™ DIAL and DPIs Instructions for Use of the In-Check™ DIAL and In-Check™ DIAL G16 (Clement Clarke International Ltd., Essex, UK) for the assessment of PIF were obtained from the Instructions for Use brochures. 30 , 31 , 36 Information regarding daily use of the following eight DPIs approved by the United States Food and Drug Administration (FDA) for use in the treatment of COPD 37–39 and prescribed in the United States at the time of the analysis was obtained from the Instructions for Use of the respective DPIs: Diskus® (GlaxoSmithKline, Research Triangle Park, NC, USA), 40 Ellipta® (GlaxoSmithKline, Research Triangle Park, NC, USA), 41 HandiHaler® (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA), 42 Neohaler® (Sunovion Pharmaceuticals Inc., Marlborough, MA, USA), 43 Pressair® (AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA), 44 RespiClick® (Teva Respiratory, LLC, Horsham, PA, USA), 45 Digihaler™ (Teva Respiratory, LLC, Frazer, PA, USA), 46 and Inhub® (Mylan Pharmaceuticals Inc., Morgantown, WV, USA). 47 Clinical and Real-Life Studies To identify how PIF was measured in various clinical and real-life studies, we conducted a PubMed search from inception to August 31, 2021, using the following search string: (“Peak inspiratory flow” OR PIF) AND (“dry powder inhaler” OR DPI). Search results were imported into an EndNote (Clarivate Analytics, Philadelphia, PA, USA) library. Abstracts and full texts were reviewed and independently verified by all authors. Reports of PIF measurement in patients with COPD using DPIs were used in the analysis. In addition, authors contributed reports from their personal libraries that were not captured during the PubMed search as applicable. Results We documented basic directions included in the Instructions for Use of the In-Check™ DIAL ( Table 2 ), daily use sections of the Instructions for Use of the eight DPIs approved by the FDA for use in COPD ( Table 3 ), and the methodology sections of published reports of studies where PIF was assessed among patients with COPD using DPIs ( Supplementary Table 1 ), as well as the thresholds for optimal and/or suboptimal PIFs from published reports of studies and the mean PIF value measured, where available ( Supplementary Table 2 ). Instructions on how to exhale before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold varied ( Tables 2 , 3 , and Supplementary Table 1 ). In many instances, instructions seemed vague and/or incomplete, and no clear guidance as to whether to measure PIF from RV or FRC was provided. Likewise, specific details regarding how PIF was measured in clinical and real-life studies were often vague, incomplete, or absent. Table 2 Instructions for Use of the In-Check™ DIAL Table 3 Instructions for Daily Use of DPIs That Are Approved by the Food and Drug Administration for the Treatment of COPD and Currently Prescribed in the United States In-Check™ DIAL How to assess whether a patient can achieve PIF within the clinically effective range of a particular DPI is outlined in the Instructions for Use of the In-Check™ DIAL ( Table 2 ). 30 , 36 A notable difference between the 2010 (In-Check™ DIAL) and 2016 (In-Check™ DIAL G16) versions of the device is the instruction recommended by the manufacturer to “exhale slowly and deeply” (2010) versus “exhale fully” (2016) before inhalation. No additional direction is provided in either instance; however, the instructions accompanying the In-Check™ G16 more closely mimic patient instructions for most DPIs. No instruction regarding the physical position of the patient’s head or body or the inhaler/In-Check™ DIAL is provided in the Instructions for Use. However, a video demonstrating the use of the In-Check™ DIAL, which shows that the device should be held horizontally during PIF measurement after exhalation, is available on the manufacturer’s website. 31 Prescribing Information of DPIs Steps for daily use of the eight DPIs are summarized in Table 3 . 40–47 Instructions for exhalation included “breathe out (exhale) as long as you can” (Diskus® and Inhub®); 40 , 47 “breathe out (exhale) fully” (Ellipta® and Neohaler®); 41 , 43 “breathe out completely in one breath, emptying your lungs of any air” (HandiHaler®); 42 “breathe out completely” (Pressair®); 44 and breathe out (exhale) through your mouth and push as much air from your lungs as you can (RespiClick® and Digihaler™). 45 , 46 Instructions for inhalation included “breathe in quickly and deeply” (Diskus®, Inhub™, RespiClick®, and Digihaler™); 40 , 45–47 “take a long, steady, deep breath” (Ellipta®); 41 “breathe in deeply until your lungs are full” (HandiHaler®); 42 “breathe in rapidly but steadily, as deeply as you can” (Neohaler®); 43 and “take a strong, deep breath” (Pressair®). 44 Instructions for patients’ head positioning were included for HandiHaler® (“hold your head in an upright position while you are looking straight ahead”) 42 and Pressair® (“hold your head upright”). 44 Instructions for patients’ body positioning were not included for any other DPI. Most Instructions for Use included the following statement: The actual amount of drug delivered to the lung will depend on patient factors, such as IF profile. 40–47 Instructions for inhaler positioning were provided for all DPIs. PIF in Published Studies Of the 128 articles retrieved, 40 were reports of studies where PIF was measured through a DPI or using the In-Check™ DIAL in patients with COPD. 7 , 8 , 12 , 20–24 , 26 , 32 , 34 , 35 , 48–75 Reports of asthma studies (n = 30); review articles (n = 10); and non-English language articles, editorials, and articles involving healthy subjects or patients with other respiratory diseases; or reports from modeling/simulations (n = 48) were excluded. An additional seven articles were included from the authors’ personal libraries; 33 , 76–81 therefore, a total of 47 reports were included in the analysis. PIF was measured using DPIs and/or inhalation profile recorders in 25 (53.2%) studies and the In-Check™ DIAL or other devices in the remaining 22 (46.8%) studies ( Supplementary Table 1 ). In most published reports of studies where PIF was measured using the In-Check™ DIAL, thresholds for optimal and/or suboptimal PIF were reported ( Supplementary Table 2 ). In a few studies, patients were reportedly seated during inhalation. 12 , 22 , 24 , 52 , 64 , 72 The position of the inhaler was reported in three studies to be vertical (Pulvinal™ and Turbuhaler®) 62 or upright (NEXThaler 70 and Turbuhaler® 74 ). The position of the patient’s head during inhalation was not reported in any study. Overall, the PIF measurement details, including inhalation instructions, were provided or participants were referred to patient information leaflets in 35 of the 47 studies (74.5%; Supplementary Table 1 ). 7 , 12 , 21–23 , 26 , 32–34 , 48 , 51–66 , 68 , 70–72 , 74–76 , 78 , 79 Instructions for exhalation before the inhalation maneuver were provided in 14 (29.8%) studies and included “exhale gently to FRC,” 12 , 26 , 60 , 66 “complete exhalation,” 21 , 23 , 57 , 74 “exhale to RV,” 60 , 75 “deeply exhale,” 62 “breathe out completely,” 74 and “breathe out as far as comfortable”. 70 In one study, PIF was measured after patients were asked to inhale as they normally do. 49 In four studies, patients were asked to inhale as they did at home with their own inhaler using the In-Check™ DIAL (with the resistance set to the specific inhaler they used), 8 , 61 , 74 , 81 and in one of these four studies, patients judged to have a weak inhalation were instructed to inhale more forcefully before another PIF measurement was taken. 61 Discussion The ability to generate an optimal IF is essential for effective aerosol drug delivery from a DPI. 8 , 18 Therefore, standardization of PIF measurements is critical to making uniform decisions in clinical practice. In this systematic evaluation of recommended and applied PIF assessment approaches, we observed considerable variations in the way patients were instructed to use their inhalers, as well as how PIF was measured in clinical and real-life studies. First, the Instructions for Use for the In-Check™ DIAL lacked specific guidance regarding the positioning of the patient’s head and body or inhaler. Likewise, steps for daily use of the eight analyzed DPIs varied in many respects and lacked in-depth instruction. Furthermore, instructions provided to patients during PIF assessments in clinical and real-life studies were diverse and often vague. In a few studies, instructions were in line with patient information leaflets/Instructions for Use brochures. 7 , 51 , 53 , 56 , 59 , 62 , 68 , 71 , 72 , 74 In other studies, the instructions were not consistent with the Instructions for Use leaflet for the DPI being evaluated. 76 , 79 The contents of the Instructions for Use of the In-Check™ DIAL were consistent with instructions provided to patients using DPIs in one study 58 but not in others. 21 , 23 In clinical studies, patients were often provided rather straightforward, but inconsistent, instructions for the inhalation maneuver; however, they were seldom clearly instructed on how to exhale beforehand. Therefore, patients were not optimally preparing for the PIF assessment. Factors such as the position of the patient’s head such that the chin is slightly upward affect drug deposition and, subsequently, outcomes in asthma. 82 The effect of posture on aerosol delivery from DPIs has not been reported. However, in a study evaluating regional lung deposition using a nebulized drug (median mass aerodynamic diameter of 4.9 µm), aerosol delivery was shifted to the bronchial airways rather than the alveolar region when the drug was administered in the supine versus seated position. 83 Differences in FRC and regional changes in ventilation accounted for these findings. We recommend that patients maintain an upright seated or erect standing position—with the chin pointed slightly upward—during the PIF assessment process. In the Instructions for Use of the In-Check™ DIAL and DPIs and in clinical and real-life studies, the definition of “full exhalation” varied. In a large observational prospective study, the ability of patients with COPD to breathe out completely in one breath was reported to be one of the most problematic steps with inhaled medication use. 84 Although exhaling completely is recommended in the Instructions for Use for most DPIs, expert opinion suggests that patients who exhale “fully and completely” (down to RV) could collapse their small airways at very low lung volumes. There are, however, no published data that support this widely held opinion other than the textbook by Bouhuys that notes that breathing at low lung volumes for prolonged periods results in atelectasis. 85 Therefore, during the subsequent inhalation phase, the “energy” generated by the inhaled breath/volume must overcome the “opening” of the collapsed small airways caused by exhaling “fully and completely.” The resultant energy available during inhalation to overcome airway collapse may be (not yet proven) inadequate to generate the required inspiratory acceleration and energy necessary to optimally activate the DPI. Although RV is a desirable measurement point, it is often difficult to assess and obtain. Furthermore, patients who are hospitalized or frequently ill are unable to exhale to RV. Therefore, considering these variabilities and potential challenges with complete exhalation, we recommend “breathing out slowly and fully,” which is generally consistent with the Instructions for Use for DPIs and can be realistically performed by a patient in a clinical setting. Although patients were generally provided with the actual direction about the inhalation maneuver in clinical studies, instructions varied. Patients were instructed to breathe in “rapidly/forcefully and deeply” in some studies, 57 , 62 , 70 , 74 , 79 but in others, they were told to take “long/hard and fast” 12 , 32 , 56 , 60 , 63 , 75 or “quick” 7 , 21 , 23 , 58 breaths. The inhalation maneuver is one of the problematic steps that could potentially lead to errors with inhaled medication use, 84 and its effect on drug deposition has been reported in several studies. 8 , 86 In studies using Diskus® and Aerolizer®, a “hard and deep” inhalation resulted in higher urinary salbutamol excretion and was recommended in patients with poor inspiratory effort, such as the elderly. 87 , 88 In a separate study, patients using indacaterol Breezhaler® (Neohaler®) were instructed to “inhale as hard and fast as they can from the start of the inhalation maneuver and for as long as possible” to maximize drug delivery. 32 PIF needs to be reached almost immediately (approximately 1 second) after the inhalation maneuver begins, and the achieved level of inspiration needs to be maintained during the entire inhalation maneuver (inspiratory profile) for effective drug release. A limitation of the In-Check™ Dial is that only PIF is measured, not the flow over the entire inspiratory profile or the timing in the inspiratory cycle when PIF is reached. Hence, at what time the patient is achieving PIF—in the first few seconds, when needed, or later—is not known. We recommend that patients should “inhale as fast, and as forcefully and deeply” as they can once their lips are sealed around the mouthpiece and should maintain this level of inhalation for as long as possible. Finally, we recommend that a maximum of three consecutive measures should be used to determine the highest PIF versus the average of two or three measures; 89 appropriate hygiene instructions should be followed for the In-Check™ DIAL; 90 and the decision to assess PIF should be made by the healthcare provider based on patient-level information (eg, health status) and guidance set forth by organizations such as the American Thoracic Society regarding pulmonary function testing. 91 , 92 We aimed to provide recommendations that are aligned with real-world experience and directions for performing spirometry 92–94 so that they are useful, practical, and ultimately beneficial to patients ( Table 4 ; https://editage.sharefile.com/share/view/s744a7fee41d149bf9f345fd8d59291a7 ). Our recommendations are largely based on the In-Check™ DIAL; recommendations for other PIF measurement devices may differ. Suboptimal PIF (ie, PIF below the optimal threshold for the selected DPI) has been widely reported, 8 , 12 , 20 , 23 can result in less than favorable outcomes, 9 and may be associated with hospital readmissions. 22 With an optimal PIF, sufficient dose of medication is more likely to be delivered, which should contribute to better clinical outcomes. Of note, however, the definition of “optimal” PIF for each individual DPI and the methods to measure PIF continue to be investigated. Table 4 Summary of Main Recommendations Limitations to our evaluation include extrapolation from in vitro data and difficulty in providing a precise cutoff for the “suboptimal” PIF for each DPI. Findings from studies attempting to correlate suboptimal PIF with clinical outcomes were inconsistent. 22 , 23 Furthermore, our recommendations are based on experience in clinical practice and require further evaluation. Studies in which the impact of different inspiratory techniques (breathing out completely vs as much as possible, sitting vs standing) on PIF measurement are lacking, and additional studies are warranted. Conclusions Our analysis of recommended and applied PIF assessment approaches revealed considerable variations in the way PIF is measured for the use of DPIs. Standardization of PIF measurements is needed because a patient’s ability to generate an optimal IF is essential for effective drug delivery from a DPI. Based on current evidence, we recommend that while in a seated position, patients comfortably exhale slowly and fully, then inhale through the mouthpiece as fast and as forcefully and deeply as they can and maintain that level of inhalation for as long as possible. If adopted, these recommendations should yield PIF measurements that are conducted in a reproducible, standardized manner, which will help clinicians select the appropriate inhaler for each patient and, if selecting a DPI, help patients achieve the optimal PIF needed for effective drug dispersal and deposition. Abbreviations COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; FDA, Food and Drug Administration; FRC, functional residual capacity; FVC, forced vital capacity; IF, inspiratory flow; PIF, peak inspiratory flow; pMDI, pressurized metered-dose inhaler; RV, residual volume; SMI, soft-mist inhaler. Acknowledgments The authors meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors. The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and formatting assistance was provided by Suchita Nath-Sain, PhD, and Maribeth Bogush, PhD, of Cactus Life Sciences (part of Cactus Communications), which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) for these services. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Author Contributions All authors contributed to the analysis and interpretation of data and critical review of the manuscript; agreed on the journal to which the manuscript will be submitted; reviewed and agreed on all versions of the manuscript before submission, during revision and the final version accepted for publication as well as any significant changes introduced at the proofing stage; and agree to take responsibility and be accountable for the contents of the article. Funding Disclosure J. A. O. reports personal fees from and serving on the advisory board of AstraZeneca, Mylan, Sunovion, Boehringer Ingelheim, GlaxoSmithKline, Hughes Hubbard Law Firm, Reckitt Benckiser, Teva, Theravance, and Verona, and has received grants from Sunovion for a clinical study outside the submitted work. G. T. F. reports grants, personal fees, and nonfinancial support from Boehringer Ingelheim, AstraZeneca, Novartis, Pearl Therapeutics, Sunovion, Teva, Theravance, and GlaxoSmithKline; personal fees from DevPro, Galderma, Mylan, Orpheris, Innoviva, and Circassia; grants and personal fees from Sanofi and Verona; and grants from Chiesi and Altavant outside the submitted work. D. A. M. serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan, Teva, Theravance, Verona, Viatris, and Sunovion; is on the speakers’ bureau for AstraZeneca, Boehringer Ingelheim, and Sunovion; and received royalties from Salem Communications Holding Corporation for COPD: Answers to Your Questions, 2014. He also reports use of baseline and transition dyspnea indexes in clinical trials from several pharmaceutical companies (2020: eResearch Technology, Inc. and Parexel International; 2021: Palobiofarma S.L. ; YPrime; and eResearch Tchnology, Inc.). M. B. D. reports grants and personal fees from Boehringer Ingelheim; personal fees from GlaxoSmithKline, AstraZeneca, Mylan-Theravance, Novavax, Parion, Midmark, and Philips; and grants from Teva and the Department of Defense and National Institutes of Health outside the submitted work. R. D. serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, Mylan-Theravance, GlaxoSmithKline, and Bayer; reports speaker fees from Boehringer Ingelheim, Teva, and Sunovion; provides manuscript support for AstraZeneca, Boehringer Ingelheim, and Bayer; and has received honorarium from UptoDate. R. A. P. reports grants from AstraZeneca; personal fees from Theravance; and grants and personal fees from Boehringer Ingelheim and Teva. A. A. reports consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Mylan-Theravance, and Teva outside the submitted work. D. M. G. H. reports personal fees from AstraZeneca, Chiesi, Novartis, Pfizer, and Sanofi; personal fees and nonfinancial support from Boehringer Ingelheim and GlaxoSmithKline outside the submitted work. D.B.P. reports advisory board membership with AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Sanofi Genzyme, Thermofisher; consultancy agreements with Airway Vista Secretariat, AstraZeneca, Boehringer Ingelheim, Chiesi, EPG Communication Holdings Ltd, FIECON Ltd, Fieldwork International, GlaxoSmithKline, Mylan, Mundipharma, Novartis, OM Pharma SA, PeerVoice, Phadia AB, Spirosure Inc, Strategic North Limited, Synapse Research Management Partners S.L., Talos Health Solutions, Theravance, and WebMD Global LLC; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance, and UK National Health Service; payment for lectures/speaking engagements from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Mundipharma, Novartis, Regeneron Pharmaceuticals, and Sanofi Genzyme; payment for travel/accommodation/meeting expenses from AstraZeneca, Boehringer Ingelheim, Mundipharma, Mylan, Novartis, and Thermofisher; and stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals. He also owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 92.61% of Observational and Pragmatic Research Institute Pte Ltd (Singapore); has 5% shareholding in Timestamp, which develops adherence monitoring technology; is a peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline. G. S. D. reports personal fees from Boehringer Ingelheim. H. M. H. has no conflicts of interest to declare. J. H. reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Circassia, and Teva outside the submitted work. M. W. H. serves on the advisory boards of Boehringer Ingelheim and Theravance; reports consulting fees from Olympus Medical; reports non-financial manuscript support from Cactus Communications, and is on the speakers’ bureau for Theravance. O. S. 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