Design Considerations for Intratracheal Delivery Devices to Achieve Proof-of-Concept Dry Powder Biopharmaceutical Delivery in Mice.

PURPOSE: Intratracheal delivery and consistent dosing of dry powder vaccines is especially challenging in mice. To address this issue, device design of positive pressure dosators and actuation parameters were assessed for their impacts on powder flowability and in vivo dry powder delivery. METHODS: A chamber-loading dosator assembled with stainless-steel, polypropylene or polytetrafluoroethylene needle-tips was used to determine optimal actuation parameters. Powder loading methods including tamp-loading, chamber-loading and pipette tip-loading were compared to assess performance of the dosator delivery device in mice. RESULTS: Available dose was highest (45%) with a stainless-steel tip loaded with an optimal mass and syringe air volume, primarily due to the ability of this configuration to dissipate static charge. However, this tip encouraged more agglomeration along its flow path in the presence of humidity and was too rigid for intubation of mice compared to a more flexible polypropylene tip. Using optimized actuation parameters, the polypropylene pipette tip-loading dosator achieved an acceptable in vivo emitted dose of 50% in mice. After administering two doses of a spray dried adenovirus encapsulated in mannitol-dextran, high bioactivity was observed in excised mouse lung tissue three days post-infection. CONCLUSIONS: This proof-of-concept study demonstrates for the first time that intratracheal delivery of a thermally stable, viral-vectored dry powder can achieve equivalent bioactivity to the same powder, reconstituted and delivered intratracheally. This work may guide the design and device selection process for murine intratracheal delivery of dry powder vaccines to help progress this promising area of inhalable therapeutics.

Dextran Mass Ratio Controls Particle Drying Dynamics in a Thermally Stable Dry Powder Vaccine for Pulmonary Delivery.

PURPOSE: Thermally stable, spray dried vaccines targeting respiratory diseases are promising candidates for pulmonary delivery, requiring careful excipient formulation to effectively encapsulate and protect labile biologics. This study investigates the impact of dextran mass ratio and molecular weight on activity retention, thermal stability and aerosol behaviour of a labile adenoviral vector (AdHu5) encapsulated within a spray dried mannitol-dextran blend. METHODS: Comparing formulations using 40 kDa or 500 kDa dextran at mass ratios of 1:3 and 3:1 mannitol to dextran, in vitro quantification of activity losses and powder flowability was used to assess suitability for inhalation. RESULTS: Incorporating mannitol in a 1:3 ratio with 500 kDa dextran reduced viral titre processing losses below 0.5 log and displayed strong thermal stability under accelerated aging conditions. Moisture absorption and agglomeration was higher in dextran-rich formulations, but under low humidity the 1:3 ratio with 500 kDa dextran powder had the lowest mass median aerodynamic diameter (4.4 µm) and 84% emitted dose from an intratracheal dosator, indicating strong aerosol performance. CONCLUSIONS: Overall, dextran-rich formulations increased viscosity during drying which slowed self-diffusion and favorably hindered viral partitioning at the particle surface. Reducing mannitol content also minimized AdHu5 exclusion from crystalline regions that can force the vector to air-solid interfaces where deactivation occurs. Although increased dextran molecular weight improved activity retention at the 1:3 ratio, it was less influential than the ratio parameter. Improving encapsulation ultimately allows inhalable vaccines to be prepared at higher potency, requiring less powder mass per inhaled dose and higher delivery efficiency.

Aerosol drug delivery: developments in device design and clinical use.

Aerosolised drugs are prescribed for use in a range of inhaler devices and systems. Delivering drugs by inhalation requires a formulation that can be successfully aerosolised and a delivery system that produces a useful aerosol of the drug; the particles or droplets need to be of sufficient size and mass to be carried to the distal lung or deposited on proximal airways to give rise to a therapeutic effect. Patients and caregivers must use and maintain these aerosol drug delivery devices correctly. In recent years, several technical innovations have led to aerosol drug delivery devices with efficient drug delivery and with novel features that take into account factors such as dose tracking, portability, materials of manufacture, breath actuation, the interface with the patient, combination therapies, and systemic delivery. These changes have improved performance in all four categories of devices: metered dose inhalers, spacers and holding chambers, dry powder inhalers, and nebulisers. Additionally, several therapies usually given by injection are now prescribed as aerosols for use in a range of drug delivery devices. In this Review, we discuss recent developments in the design and clinical use of aerosol devices over the past 10-15 years with an emphasis on the treatment of respiratory disorders.

Radiolabeling Methods.

In vivo measurements of the deposition of an inhaled radiolabeled pharmaceutic have provided useful information related to the inhaler efficiency for depositing drug in the lung. A number of labeling techniques have been developed and applied to pharmaceutical aerosols delivered by pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers; the choice of radiotracer depends on the type of imaging study being performed and the equipment used to image the lung. Preparation, validation and calibration of the radiolabeled pharmaceutical product is key to successful interpretation of the imaging study. When imaging a subject after inhalation of a radiolabeled formulation, it is the radioactivity that is detected and measured by the scanner; absolute amounts of deposited drug are inferred from the counts of radioactivity in the lung and other regions, based on the assumption that there is a 1:1 relationship between the two components-drug and radioactivity. This relationship holds true for direct-labeled PET products or for those formulations where a firm bond can be demonstrated between the drug and radiotracer for the time taken to acquire all the images. This chapter will discuss radiolabeling methods applied to therapeutic aerosols for the purpose of determining the deposition efficiency of these aerosols in the lung. The techniques apply to both in vivo studies in man and in animal models, and to some extent to in vitro models.

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Forgotten Technology in the COVID-19 Pandemic: Filtration Properties of Cloth and Cloth Masks-A Narrative Review.

Management of the global crisis of the coronavirus disease 2019 pandemic requires detailed appraisal of evidence to support clear, actionable, and consistent public health messaging. The use of cloth masks for general public use is being debated, and is in flux. We searched the MEDLINE and EMBASE databases and Google for articles reporting the filtration properties of flat cloth or cloth masks. We reviewed the reference lists of relevant articles to identify further articles and identified articles through social and conventional news media. We found 25 articles. Study of protection for the wearer used healthy volunteers, or used a manikin wearing a mask, with airflow to simulate different breathing rates. Studies of protection of the environment, also known as source control, used convenience samples of healthy volunteers. The design and execution of the studies was generally rigorously described. Many descriptions of cloth lacked the detail required for reproducibility; no study provided all the expected details of material, thread count, weave, and weight. Some of the homemade mask designs were reproducible. Successful masks were made of muslin at 100 threads per inch (TPI) in 3 to 4 layers (4-layer muslin or a muslin-flannel-muslin sandwich), tea towels (also known as dish towels), made using 1 layer (2 layers would be expected to be better), and good-quality cotton T-shirts in 2 layers (with a stitched edge to prevent stretching). In flat-cloth experiments, linen tea towels, 600-TPI cotton in 2 layers, and 600-TPI cotton with 90-TPI flannel performed well but 80-TPI cotton in 2 layers did not. We therefore recommend cotton or flannel at least 100 TPI, at least 2 layers. More layers, 3 or 4, will provide increased filtration but there is a trade-off in that more layers increases the resistance to breathing. Although this is not a systematic review, we included all the articles that we identified in an unbiased way. We did not include gray literature or preprints. A plain language summary of these data and recommendations, as well as information on making, wearing and cleaning cloth masks is available at www.clothmasks.ca.

Studies of Radioaerosol Deposition in the Respiratory Tract.

Deposition of aerosols in the respiratory tract can be quantitatively and qualitatively studied by scintigraphy. The most commonly used radionuclide for this purpose is technetium-99m. The effects of various factors on particle deposition have been investigated by using radiolabeled aerosols in the past decade. Most of these studies were in vivo but some were in vitro or ex vivo. The factors examined include particle size, formulation, inhaler design, inhalation flowrate, body posture, and gravity. They have been shown to influence pulmonary deposition, nasal high flow nebulization, and intranasal delivery. A thorough understanding of the various factors is required for the advancement of respiratory-drug delivery. Scintigraphy is a powerful technique that can assist in this regard.

Biophysical model to predict lung delivery from a dual bronchodilator dry-powder inhaler.

A biophysical lung model was designed to predict inhaled drug deposition in patients with obstructive airway disease, and quantitatively investigate sources of deposition variability. Different mouth-throat anatomies at varying simulated inhalation flows were used to calculate the lung dose of indacaterol/glycopyrronium [IND/GLY] 110/50 µg (QVA149) from the dry-powder inhaler Breezhaler®. Sources of variability in lung dose were studied using computational fluid dynamics, supported by aerosol particle sizing measurements, particle image velocimetry and computed tomography. Anatomical differences in mouth-throat geometries were identified as a major source of inter-subject variability in lung deposition. Lung dose was similar across inhalation flows of 30-120 L/min with a slight drop in calculated delivery at high inspiratory flows. Delivery was relatively unaffected by inhaler inclination angle. The delivered lung dose of the fixed-dose combination IND/GLY matched well with corresponding monotherapy doses. This biophysical model indicates low extra-thoracic drug loss and consistent lung delivery of IND/GLY, independent of inhalation flows. This is an important finding for patients across various ages and lung disease severities. The model provides a quantitative, mechanistic simulation of inhaled therapies that could provide a test system for estimating drug delivery to the lung and complement traditional clinical studies.

Errors in the Use of Inhalers by Health Care Professionals: A Systematic Review.

BACKGROUND: Inefficient inhaler technique (IT) compromises the optimal delivery of medication. However, the IT knowledge of health care professionals (HCPs) has received scant attention. OBJECTIVE: The objective of this study was to perform a systematic review of published reports assessing the IT proficiency of HCPs in using pressurized metered dose (pMDI) and dry powder (DPI) inhalers. METHODS: Studies published between 1975 and 2014 that directly assessed the IT skills of HCPs were selected according to predefined selection criteria. RESULTS: Data were extracted from 55 studies involving 6,304 HCPs who performed 9,996 tests to demonstrate their IT proficiency. Overall, the IT was considered correct in 15.5% of cases (95% confidence interval [CI], 12-19.3), decreasing over time from 20.5% (95% CI, 14.9-26.8) from the early period (defined as 1975-1995) to 10.8% (95% CI, 7.3-14.8) during the late period (1996-2014). The most common errors in the use of pMDIs were as follows: not breathing out completely before inhalation (75%; 95% CI, 56-90), lack of coordination (64%; 95% CI, 29-92), and postinhalation breath-hold (63%; 95% CI, 52-72). The most common errors using DPI were deficient preparation (89%; 95% CI, 82-95), not breathing out completely before inhalation (79%; 95% CI, 68-87), and no breath-hold (76%; 95% CI, 67-84). CONCLUSIONS: HCPs demonstrated inadequate knowledge of the proper use of inhalers. The poor understanding of the correct use of these devices may prevent these professionals from being able to adequately assess and teach proper inhalation techniques to their patients.

Relationship of Inhaled Corticosteroid Adherence to Asthma Exacerbations in Patients with Moderate-to-Severe Asthma.

BACKGROUND: Patients with asthma and elevated blood eosinophils are at increased risk of severe exacerbations. Management of these patients should consider nonadherence to inhaled corticosteroid (ICS) therapy as a factor for increased exacerbation risk. OBJECTIVE: The objective of this study was to investigate whether poor adherence to ICS therapy explains the occurrence of asthma exacerbations in patients with elevated blood eosinophil levels. METHODS: This historical cohort study identified patients within the Optimum Patient Care Research Database, aged 18 years or more, at Global Initiative for Asthma step 3 or 4, with 2 or more ICS prescriptions during the year before the clinical review. Patient characteristics and adherence (based on prescription refills and patient self-report) for ICS therapy were analyzed for those with elevated (>400 cells/µL) or normal (≤400 cells/µL) blood eosinophils. RESULTS: We studied 7195 patients (66% female, mean age 60 years) with median eosinophil count of 200 cells/µL and found 81% to be not fully adherent to ICS therapy. A total of 1031 patients (14%) had elevated blood eosinophil counts (58% female, mean age 60 years), 83% of whom were not fully adherent to ICS. An increased proportion of adherent patients in the elevated blood eosinophil group had 2 or more exacerbations (14.0% vs 7.2%; P = .003) and uncontrolled asthma (73% vs 60.8%; P = .004) as compared with non-fully adherent patients. CONCLUSIONS: Approximately 1 in 7 patients had elevated eosinophils. Adherence to ICS therapy was not associated with decreased exacerbations for these patients. Additional therapy should be considered for these patients, such as biologics, which have been previously shown to improve control in severe uncontrolled eosinophilic asthma.

The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes.

BACKGROUND: Patients with COPD may be prescribed multiple inhalers as part of their treatment regimen, which require different inhalation techniques. Previous literature has shown that the effectiveness of inhaled treatment can be adversely affected by incorrect inhaler technique. Prescribing a range of device types could worsen this problem, leading to poorer outcomes in COPD patients, but the impact is not yet known. AIMS: To compare clinical outcomes of COPD patients who use devices requiring similar inhalation technique with those who use devices with mixed techniques. METHODS: A matched cohort design was used, with 2 years of data from the Optimum Patient Care Research Database. Matching variables were established from a baseline year of follow-up data, and two cohorts were formed: a "similar-devices cohort" and a "mixed-devices cohort". COPD-related events were recorded during an outcome year of follow-up. The primary outcome measure was an incidence rate ratio (IRR) comparing the rate of exacerbations between study cohorts. A secondary outcome compared average daily use of short-acting beta agonist (SABA). RESULTS: The final study sample contained 8,225 patients in each cohort (mean age 67 [SD, 10], 57% males, 37% current smokers). Patients in the similar-devices cohort had a lower rate of exacerbations compared with those in the mixed-devices cohort (adjusted IRR 0.82, 95% confidence interval [CI] 0.80-0.84) and were less likely to be in a higher-dose SABA group (adjusted proportional odds ratio 0.54, 95% CI 0.51-0.57). CONCLUSION: COPD patients who were prescribed one or more additional inhaler devices requiring similar inhalation techniques to their previous device(s) showed better outcomes than those who were prescribed devices requiring different techniques.

Real-Life Outcomes for Patients with Asthma Prescribed Spacers for Use with Either Extrafine- or Fine-Particle Inhaled Corticosteroids.

BACKGROUND: Spacers are often used with pressurized metered-dose inhalers (pMDIs) to eliminate the need for coordinating inhalation with actuation. OBJECTIVE: To investigate the real-life effectiveness of spacers prescribed for use with either extrafine- or fine-particle inhaled corticosteroids (ICSs). METHODS: This historical matched cohort study examined anonymous medical record data over 2 years (1-year baseline, 1-year outcome) for patients with asthma aged 12 to 80 years initiating ICSs by pMDI with or without prescribed spacer. We compared outcomes for spacer versus no-spacer arms, matched for key baseline and asthma-related characteristics, within 2 ICS cohorts: (1) extrafine-particle ICS (beclomethasone) and (2) fine-particle ICS (fluticasone). Effectiveness end points were compared using conditional regression methods. RESULTS: Matched spacer and no-spacer arms of the extrafine-particle ICS cohort each included 2090 patients (69% females; median age, 46-47 years) and the 2 arms of the fine-particle ICS cohort each included 444 patients (67% females; median age, 45 years). With extrafine-particle ICS, we observed no significant difference between spacer and no-spacer arms in severe exacerbation rate (primary end point): adjusted rate ratio, 1.01 (95% CI, 0.83-1.23). With fine-particle ICS, the severe exacerbation rate ratio with spacers was 0.77 (0.47-1.25). Oropharyngeal candidiasis incidence was low and similar in spacer and no-spacer arms for both ICS cohorts. CONCLUSIONS: We found no evidence that prescribed spacer devices are associated with improved asthma outcomes for extrafine- or fine-particle ICS administered by pMDI. These findings challenge long-standing assumptions that spacers should improve pMDI effectiveness and indicate the need for pragmatic trials of spacers in clinical practice.

Patient Focus and Regulatory Considerations for Inhalation Device Design: Report from the 2015 IPAC-RS/ISAM Workshop.

This article reports on discussions at the 2015 workshop cosponsored by the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) and the International Society for Aerosols in Medicine (ISAM), entitled "Regulatory and Patient Considerations for Inhalation Device Design, Development and Use." Key topics addressed at the workshop and presented here include patient-focused device design for orally inhaled products (OIPs), instructions for use (IFU), human factors, regulatory considerations in the United States and Europe, development of generic inhalers, quality-by-design, and change management of OIP devices. Workshop participants also identified several areas for further consideration and emphasized the need for increased focus on the patient to create therapeutic products (inclusive of device design, IFU, education, training) that support adherence with an individual patient's treatment regimen. Advances in patient-centric product development will require engagement and collaboration by industry, regulators, patients, physicians, and other stakeholders. The article includes summaries of presented talks as well as of panel and audience discussions.

Airway Epithelial Cell Cilia and Obstructive Lung Disease.

Airway epithelium is the first line of defense against exposure of the airway and lung to various inflammatory stimuli. Ciliary beating of airway epithelial cells constitutes an important part of the mucociliary transport apparatus. To be effective in transporting secretions out of the lung, the mucociliary transport apparatus must exhibit a cohesive beating of all ciliated epithelial cells that line the upper and lower respiratory tract. Cilia function can be modulated by exposures to endogenous and exogenous factors and by the viscosity of the mucus lining the epithelium. Cilia function is impaired in lung diseases such as COPD and asthma, and pharmacologic agents can modulate cilia function and mucus viscosity. Cilia beating is reduced in COPD, however, more research is needed to determine the structural-functional regulation of ciliary beating via all signaling pathways and how this might relate to the initiation or progression of obstructive lung diseases. Additionally, genotypes and how these can influence phenotypes and epithelial cell cilia function and structure should be taken into consideration in future investigations.

Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology.

BACKGROUND: The proliferation of inhaler devices has resulted in a confusing number of choices for clinicians who are selecting a delivery device for aerosol therapy. There are advantages and disadvantages associated with each device category. Evidence-based guidelines for the selection of the appropriate aerosol delivery device in specific clinical settings are needed. AIM: (1) To compare the efficacy and adverse effects of treatment using nebulizers vs pressurized metered-dose inhalers (MDIs) with or without a spacer/holding chamber vs dry powder inhalers (DPIs) as delivery systems for beta-agonists, anticholinergic agents, and corticosteroids for several commonly encountered clinical settings and patient populations, and (2) to provide recommendations to clinicians to aid them in selecting a particular aerosol delivery device for their patients. METHODS: A systematic review of pertinent randomized, controlled clinical trials (RCTs) was undertaken using MEDLINE, EmBase, and the Cochrane Library databases. A broad search strategy was chosen, combining terms related to aerosol devices or drugs with the diseases of interest in various patient groups and clinical settings. Only RCTs in which the same drug was administered with different devices were included. RCTs (394 trials) assessing inhaled corticosteroid, beta2-agonist, and anticholinergic agents delivered by an MDI, an MDI with a spacer/holding chamber, a nebulizer, or a DPI were identified for the years 1982 to 2001. A total of 254 outcomes were tabulated. Of the 131 studies that met the eligibility criteria, only 59 (primarily those that tested beta2-agonists) proved to have useable data. RESULTS: None of the pooled metaanalyses showed a significant difference between devices in any efficacy outcome in any patient group for each of the clinical settings that was investigated. The adverse effects that were reported were minimal and were related to the increased drug dose that was delivered. Each of the delivery devices provided similar outcomes in patients using the correct technique for inhalation. CONCLUSIONS: Devices used for the delivery of bronchodilators and steroids can be equally efficacious. When selecting an aerosol delivery device for patients with asthma and COPD, the following should be considered: device/drug availability; clinical setting; patient age and the ability to use the selected device correctly; device use with multiple medications; cost and reimbursement; drug administration time; convenience in both outpatient and inpatient settings; and physician and patient preference.

In vitro estimations of in vivo jet nebulizer efficiency using actual and simulated tidal breathing patterns.

In vivo aerosol delivery efficiency was estimated in vitro for two jet nebulizers using a breath monitor (Breathe!; Pari GmbH, Germany) and breath simulator (COMPAS; Pari GmbH) to reproduce subject tidal breathing patterns. The AeroEclipse (Trudell Medical International, Canada), a breath-actuated nebulizer, and the LC Star (Pari GmbH), a breath-enhanced nebulizer, were filled with levalbuterol HCl solution (Sepracor, USA) and operated with compressed O(2) at 8 lpm. Tidal breathing patterns of 20 adult subjects were digitally recorded with the Breathe! Breath Monitor. Subjects then breathed tidally from each nebulizer separately for 1 minute and to nebulizer dryness. Levalbuterol aerosol collected on filters placed between the nebulizer and mouth was chemically assayed to determine the inspired mass (IM), wasted mass (WM) and total emitted mass (TM). Measurements were repeated using the COMPAS Breath Simulator to simulate each subject's tidal breathing pattern. IM, WM, and TM measurements using actual versus simulated tidal breathing were highly comparable for each nebulizer, except the IM (p < 0.05) from LC Star measured at nebulizer dryness. Breath simulation was an inaccurate tool for estimating the time to nebulizer dryness as simulated measurements to nebulizer dryness took significantly longer than measurements preformed with actual tidal breathing (p < 0.001). While breath simulation provides an accurate in vitro tool for estimating in vivo aerosol delivery, it should not completely replace in vivo measurements until inherent limitations in simulator operation can be overcome to provide a more clinically realistic simulation.

Assessing nebulizer performance.

The quality of the aerosol generated by a nebulizer system is a function of its design, operating parameters, and the drug formulation to be aerosolized. The aerosolized drug dose inhaled from a nebulizer is determined by the patient's breathing pattern. The site of deposition of the aerosol in the lung is primarily influenced by the inspiratory flow rate and additionally by the nature of the lung disease. Thus, tests of performance that incorporate these different variables will provide data that give a better understanding of overall nebulizer performance. As discussed in this paper, a number of in vitro and in vivo laboratory tests can be undertaken to measure the characteristics of the delivery system as well as the quality and quantity of the aerosolized drug provided. With this information one can estimate the dose of drug that will be inhaled and deposited below the larynx. The accuracy of these predictions can additionally be improved with the use of breath simulators and standard breath patterns. Breath monitors that capture and feed actual patient breathing patterns into the simulator to mimic nebulizer operation during actual patient use further increase the accuracy of dose estimation. With the vast number of nebulizers available and also in development, a comparison of information obtained from different nebulizers is key in making an informed decision when selecting an aerosol delivery system that can provide an efficacious dose of a particular drug to a specific patient population.