Validation of a general in vitro approach for prediction of total lung deposition in healthy adults for pharmaceutical inhalation products.

BACKGROUND: A validated method to predict lung deposition for inhaled medication from in vitro data is lacking in spite of many attempts to correlate in vitro and in vivo outcomes. By using an in vivo-like in vitro setup and analyzing inhalers from the same batches, both in vitro and in vivo, we wanted to create a situation where information from the in vitro and in vivo outcomes could be analyzed at the same time. METHOD: Nine inhalation products containing either budesonide or AZD4818 were evaluated. These comprised two pressurized metered dose inhalers (pMDIs), a pMDI plus a spacer, four dry powder inhalers, and two dosimetric nebulizers. In vitro, an in vivo-like setup consisting of anatomically correct inlet throats were linked to a flow system that could replay actual inhalation flow profiles through the throat to a filter or to an impactor. In vivo, total lung deposition was measured in healthy adults by pharmacokinetic methods. RESULTS AND CONCLUSION: We could show that the amount of drug escaping filtration in a realistic throat model under realistic delivery conditions predicts the typical total lung deposition in trained healthy adult subjects in the absence of significant exhaled mass. We could further show that by using combinations of throat models and flow profiles that represent realistic deviations from the typical case, variations in ex-cast deposition reflect between-subject variation in lung deposition. Further, we have demonstrated that ex-cast deposition collected either by a simple filter or by a cascade impactor operated at a fixed flow rate using a mixing inlet, to accommodate a variable flow profile through the inhaler, predicts equally well the lung deposited dose. Additionally, the ex-cast particle size distribution measured by this method may be relevant for predicting exhaled fraction and regional lung deposition by computational models.

Deposition, imaging, and clearance: what remains to be done?

Deposition and clearance studies are used during product development and in fundamental research. These studies mostly involve radionuclide imaging, but pharmacokinetic methods are also used to assess the amount of drug absorbed through the lungs, which is closely related to lung deposition. Radionuclide imaging may be two-dimensional (gamma scintigraphy or planar imaging), or three-dimensional (single photon emission computed tomography and positron emission tomography). In October 2009, a group of scientists met at the "Thousand Years of Pharmaceutical Aerosols" conference in Reykjavik, Iceland, to discuss future research in key areas of pulmonary drug delivery. This article reports the session on "Deposition, imaging and clearance." The objective was partly to review our current understanding, but more importantly to assess "what remains to be done?" A need to standardize methodology and provide a regulatory framework by which data from radionuclide imaging methods could be compared between centers and used in the drug approval process was recognized. There is also a requirement for novel radiolabeling methods that are more representative of production processes for dry powder inhalers and pressurized metered dose inhalers. A need was identified for studies to aid our understanding of the relationship between clinical effects and regional deposition patterns of inhaled drugs. A robust methodology to assess clearance from small conducting airways should be developed, as a potential biomarker for therapies in cystic fibrosis and other diseases. The mechanisms by which inhaled nanoparticles are removed from the lungs, and the factors on which their removal depends, require further investigation. Last, and by no means least, we need a better understanding of patient-related factors, including how to reduce the variability in pulmonary drug delivery, in order to improve the precision of deposition and clearance measurements.

The bioavailability and airway clearance of the steroid component of budesonide/formoterol and salmeterol/fluticasone after inhaled administration in patients with COPD and healthy subjects: a randomized controlled trial.

BACKGROUND: Airway absorption and bioavailability of inhaled corticosteroids (ICSs) may be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in patients with severe chronic obstructive pulmonary disease (COPD) by measuring the systemic availability and sputum concentration of budesonide and fluticasone, administered via combination inhalers with the respective long-acting beta2-agonists, formoterol and salmeterol. METHODS: This was a randomized, double-blind, double-dummy, two-way crossover, multicenter study. Following a run-in period, 28 patients with severe COPD (mean age 65 years, mean forced expiratory volume in 1 second [FEV1] 37.5% predicted normal) and 27 healthy subjects (mean age 31 years, FEV1 103.3% predicted normal) received two single-dose treatments of budesonide/formoterol (400/12 microg) and salmeterol/fluticasone (50/500 microg), separated by a 4-14-day washout period. ICS concentrations were measured over 10 hours post-inhalation in plasma in all subjects, and over 6 hours in spontaneously expectorated sputum in COPD patients. The primary end point was the area under the curve (AUC) of budesonide and fluticasone plasma concentrations in COPD patients relative to healthy subjects. RESULTS: Mean plasma AUC values were lower in COPD patients versus healthy subjects for budesonide (3.07 microM x hr versus 6.21 microM x hr) and fluticasone (0.84 microM x hr versus 1.50 microM x hr), and the dose-adjusted AUC (geometric mean) ratios in healthy subjects and patients with severe COPD for plasma budesonide and fluticasone were similar (2.02 versus 1.80; primary end point). In COPD patients, the Tmax and the mean residence time in the systemic circulation were shorter for budesonide versus fluticasone (15.5 min versus 50.8 min and 4.41 hrs versus 12.78 hrs, respectively) and Cmax was higher (1.08 microM versus 0.09 microM). The amount of expectorated fluticasone (percentage of estimated lung-deposited dose) in sputum over 6 hours was significantly higher versus budesonide (ratio 5.21; p = 0.006). Both treatments were well tolerated. CONCLUSION: The relative systemic availabilities of budesonide and fluticasone between patients with severe COPD and healthy subjects were similar. In patients with COPD, a larger fraction of fluticasone was expectorated in the sputum as compared with budesonide. TRIAL REGISTRATION: Trial registration number NCT00379028.

Use of dry powder inhalers in acute exacerbations of asthma and COPD.

To investigate whether dry powder inhalers (DPIs) function in a constrained situation, a literature analysis was performed to evaluate the use of DPIs compared with established therapies in the treatment of acute asthma and COPD, irrespective of rapid-acting beta(2)-agonist used. The external databases Medline, Embase, Biosis and Current Contents and AstraZeneca's internal literature database Planet were searched up to April 2008. Only publications or congress abstracts describing clinical trials in patients treated at EDs or hospitals were considered, and then only those in which exacerbation severity (measured as FEV(1)) were included. Fifteen clinical studies met these criteria; twelve in acute asthma and three in acute COPD. For acute asthma, eight studies were double-blind, randomised studies (six in adults and two in children), two were open-label studies (one in adults and one in children), and two were investigational (methacholine challenge) studies. For the acute COPD studies, one was double-blind and randomised, one was single-blind and randomised, and one was open-label. This review found that administration of fast-acting bronchodilators via DPIs, the majority of which were Turbuhaler, is effective during an asthma or COPD worsening. Our literature review finds that DPIs function in patients with acute asthma or COPD equally well as established therapies with other inhaler devices. Patients can therefore rely upon DPIs in the same way that they rely upon other inhaler devices.

Pharmacokinetics of budesonide and formoterol administered via 1 pressurized metered-dose inhaler in patients with asthma and COPD.

In 3 open-label studies, the systemic bioavailability of budesonide and formoterol administered via pressurized metered-dose inhaler (pMDI) or dry powder inhaler (DPI) formulations was evaluated in asthma (24 children, 55 adults) or chronic obstructive pulmonary disease (COPD; n = 26) patients. Treatments were administered at doses high enough to estimate pharmacokinetic parameters reliably. Two of the studies included an experimental budesonide pMDI formulation. In study 1 (asthma, adults), budesonide area under the curve (AUC) was 32% and 31% lower and maximal budesonide concentration (C(max)) 45% and 56% lower after budesonide/formoterol pMDI and budesonide pMDI versus budesonide DPI. Formoterol AUC and C(max) were 13% and 39% lower after budesonide/formoterol pMDI versus formoterol DPI. In study 2 (asthma, children), budesonide AUC and C(max) were 27% and 41% lower after budesonide/formoterol pMDI versus budesonide DPI + formoterol DPI. In study 3 (COPD/asthma, adults), budesonide AUC and C(max) were similar and formoterol AUC and C(max) 18% and 22% greater after budesonide/formoterol pMDI versus budesonide pMDI + formoterol DPI (COPD). Budesonide and formoterol AUC were 12% and 15% higher in COPD versus asthma patients. In conclusion, systemic exposure generally is similar or lower with budesonide/formoterol pMDI versus combination therapy via separate DPIs or monotherapy and comparable between asthma and COPD patients.

Sustained mechanical and clinical functionality of the flexhaler dry powder inhaler.

Flexhaler is a multiple-dose, inspiratory flow-driven dry powder inhaler that is a newer version of Turbuhaler, and is identical to the Symbicort Turbuhaler. Sustained performance is of the utmost importance to ensure consistent drug delivery throughout the lifespan of the inhaler. We report functionality testing results of Flexhaler inhalers used in two large-scale 12-week studies of budesonide (Pulmicort) and returned for testing. Functionality tests included measurement of airflow resistance and inspection of vital parts for the mechanical functionality of the inhaler, including visual inspection of the indicator wheel and function check of dose loading. In addition, delivered dose, particle size distribution, moisture content, and microbial counts were evaluated. Seven hundred sixteen out of 720 units were returned. Airflow resistance was not affected by the handling of the Flexhaler inhalers during use (prior to use, average airflow resistance: 67 Pa(0.5)*s*L(-1); returned inhalers: 66 and 67 Pa(0.5)*s*L(-1) in each study, respectively. The average dose delivered remained as intended after prolonged clinical use [95% (range 88 -103%) vs. reference of 99% (range 93-104%) before issue]. Relative fine particle dose ( <5 mum) after use was 107% (range 96-111%) of the reference value before issue. Moisture content in the inhaler desiccant was 3-25%, suggesting variability in storage conditions. Among the 28 inhalers randomly selected for microbiological testing there was no or very limited microbial growth. All 14 inhalers returned with functionality issues operated as intended and no reported functionality issues could be confirmed. Flexhaler inhalers operated as intended during these two clinical trials. These results should reassure both clinicians and patients with respect to the consistent quality of this unit for the delivery of dry powder formulations for inhalation.

Pharmacokinetics of budesonide and formoterol administered via a series of single-drug and combination inhalers: four open-label, randomized, crossover studies in healthy adults.

OBJECTIVE: To investigate the pharmacokinetics of budesonide and formoterol administered concomitantly in healthy adults. METHODS: Three single-dose, open-label crossover studies (n=28 each) were conducted (Study I: budesonide pMDI, formoterol DPI, budesonide pMDI+formoterol DPI; Study II: budesonide/formoterol pMDI, budesonide pMDI+formoterol DPI; Study III: budesonide/formoterol pMDI [three budesonide formulation strengths; constant formoterol]). Study IV (n=28) assessed steady state pharmacokinetics (budesonide/formoterol pMDI [two/four inhalations twice daily, 5-day treatment; four inhalations, single-dose]). RESULTS: Study I: no pharmacokinetic interactions were observed between budesonide and formoterol. Study II: AUC ratios were 97.9% (budesonide) and 82.2% (formoterol) (budesonide/formoterol pMDI versus budesonide pMDI+formoterol DPI). Study III: formoterol AUC was comparable across budesonide/formoterol pMDI formulation strengths; budesonide AUC increased with formulation strength in proportion to fine particle dose. Study IV: dose proportionality was demonstrated for budesonide (AUC ratio, 104.3%) and suggested for formoterol (AUC ratio, 117.6%) with budesonide/formoterol pMDI (steady state); budesonide and formoterol AUC was higher with repeated versus single-dose budesonide/formoterol pMDI (four inhalations). CONCLUSIONS: No pharmacokinetic interactions were observed between budesonide and formoterol. Budesonide dose variation in budesonide/formoterol pMDI did not affect formoterol exposure. Steady state budesonide/formoterol pMDI dose-doubling yielded proportional increases in budesonide and formoterol exposure.

Do airway clearance mechanisms influence the local and systemic effects of inhaled corticosteroids?

The role of airway clearance in inhaled drug therapy is complex. Disease-induced bronchoconstriction results in a central drug-deposition pattern where mucociliary clearance is most efficient. When drug-induced bronchodilation is achieved, deposition and uptake becomes more peripheral, and because there is less mucociliary clearance in the periphery, this will lead to an unintentional increase in lung exposure and enhance the risk of systemic side effects. In addition, mucociliary clearance is pathologically reduced in both asthma and chronic obstructive pulmonary disease. Among inhaled corticosteroids, rate of dissolution and lung uptake differs considerably. For the slowly dissolving, lipophilic steroids, the contribution of mucociliary clearance to these findings appears significant, and variability in lung and systemic exposure resulting from variable mucociliary function appears to be amplified. In addition, dose optimisation of non-stable asthma becomes more complex. The present review highlights the impact of mucociliary clearance on inhaled corticosteroid disposition and identifies critical areas where more research is needed.

Studies of the human oropharyngeal airspaces using magnetic resonance imaging IV--the oropharyngeal retention effect for four inhalation delivery systems.

Magnetic resonance imaging (MRI) of the oropharyngeal region from 20 adult volunteers using four model inhalation devices (varying mouthpiece diameters, airflow resistances) and tidal breathing was carried out. Statistical analysis (convex hull method) selected 12 scans from 80 data sets representing the extremes of all dimensions in the population. Twelve physical mouth-throat models were made by stereolithography using the exact scan data. The aim was to produce models with varying dimensions to span the adult population, and to investigate if oropharyngeal dimensions affected throat retention for different delivery systems. In an in vitro analysis, the models were used to determine the retention effect of the oropharyngeal airspaces when drug aerosols were administered from four inhalation delivery systems: a pressurised metered dose inhaler (pMDI), two different dry powder inhalers (DPIs A and B), and a nebulizer. The aims of this work were to determine the key parameters governing mouth-throat retention and whether retention was dependent on the delivery system used. Characterizing the throat models by measuring 51 different dimensional variables enabled determination of the most influential variables for dose retention for each inhalation delivery system. Throat model retention was found to be dependent on the delivery system (pMDI approximately DPI(A) > DPI(B) > Neb.). The most influential variable was the total throat model volume. Throat models representing high, median, and low oropharyngeal filtration in healthy adults have been identified.

Lung deposition and efficacy of inhaled formoterol in patients with moderate to severe COPD.

BACKGROUND: Little is known about the impact of COPD on lung deposition of inhaled drugs and the relationship between lung-dose and response of pulmonary function measurements. METHODS: Nineteen patients with varying degrees of COPD were randomized to inhale single doses of formoterol (Oxis) Turbuhaler 4.5, 9, 18, and 36 microg in a double blind, placebo-controlled, crossover design. Urinary excreted formoterol during 32 h was used to determine absolute lung deposition. Peak inspiratory flow (PIF) and inhaled volume (IV) were recorded to assess the patients' ability to use Turbuhaler. Efficacy was measured by spirometry, inspiratory capacity (IC), airway conductance (sG(AW)), and absolute lung volumes. RESULTS: Mean pulmonary bioavailability of formoterol was about 24% of the nominal delivered dose after inhalation for the different treatments. No significant correlations between lung deposition and baseline FEV(1), PIF or IV were shown. All formoterol doses produced statistically significant increases in FEV(1), FVC, IC, and sG(AW) relative to placebo. Linear dose/response relationships were observed for these variables, with more narrow limits of the slopes for the lung-dose/response relationships than for the nominal-dose/response relationships. Moreover, 36 and 18 microg formoterol statistically significantly decreased functional residual capacity (FRC) and residual volume (RV) relative to placebo. CONCLUSIONS: This study could not show any difference in lung deposition of formoterol inhaled via Turbuhaler between patients with moderate and severe COPD. Moreover, the effect of formoterol on various pulmonary function measurements were more closely related to lung deposition than the inhaled nominal dose.

Performance of Turbuhaler((R)) in Patients with Acute Airway Obstruction and COPD, and in Children with Asthma : Understanding the Clinical Importance of Adequate Peak Inspiratory Flow, High Lung Deposition, and Low In Vivo Dose Variability.

The dry-powder inhaler (DPI) Turbuhaler((R)) has been on the market for nearly two decades. Products containing terbutaline, formoterol, budesonide, and the combination budesonide/formoterol are widely used by patients with asthma and COPD. Most patients and physicians find Turbuhaler((R)) easy to use, and local side effects are rare. This is thought to arise from the lack of additives or only small amounts in the formulation, in addition to minimal deposition of the drug in the oropharynx and on the vocal cords during inspiration.The function of Turbuhaler((R)) has frequently been questioned. This article aims to review and clarify some key issues that have been challenged in the literature (e.g. the effectiveness of Turbuhaler((R)) in patients with more restricting conditions), to discuss the importance of lung deposition, and to explain the low in vivo variability associated with Turbuhaler((R)) and the lack of correlation with the higher in vitro variability.Turbuhaler((R)), like other DPIs, is flow dependent to some degree. However, a peak inspiratory flow (PIF) through Turbuhaler((R)) of 30 L/min gives a good clinical effect. These PIF values can be obtained by patients with conditions thought to be difficult to manage with inhalational agents, such as asthmatic children and adult patients with acute severe airway obstruction and COPD. Excellent clinical results with Turbuhaler((R)) in large controlled studies in patients with COPD and acute severe airway obstruction provide indirect evidence that medication delivered via Turbuhaler((R)) reaches the target organ.Due to the large amount of small particles and the moderate inbuilt resistance in Turbuhaler((R)), which opens up the vocal cords during inhalation, Turbuhaler((R)) is associated with a high lung deposition (25-40% of the delivered dose) compared with pressurized metered-dose inhalers (pMDIs) and other DPIs. A good correlation has been found between lung deposition and clinical efficacy. A high lung deposition always results in the best ratio between clinical efficacy and risk of unwanted systemic activity. Studies with Turbuhaler((R)) also show that the in vivo variation in lung deposition is significantly lower compared with a pMDI or, for example, the Diskus((R)) inhaler, and much lower than the in vitro dose variability seen in laboratory tests. Turbuhaler((R)) appears to be a reliable DPI which can be used with confidence by patients with airway diseases, including those with clinical conditions believed to be difficult to manage with inhalational therapy.

Degree of throat deposition can explain the variability in lung deposition of inhaled drugs.

Inhalation is a mainstay for treatment of asthma, and lung deposition can be seen as a surrogate marker for the ensuing clinical effects. Not only absolute lung deposition, but also its variability is of interest, as it indicates the range of expected lung deposition in an individual patient when prescribing the drug and the expected day-to-day variability when using it. A literature survey found 71 studies with relevant information on lung deposition and its variability. Further characteristics of the studies, such as if the subjects were healthy or asthmatics, adults or children, and what device that was used, were noted. In all, 187 data points were included. Variability in lung deposition was depicted as a function of mean lung deposition; for the entire data set and for subsets thereof. Independent of device type or subject category high lung deposition was associated with low relative variability and vice versa. Using a published throat deposition model, the observed correlation of lung deposition variability to mean lung deposition could be explained as being determined largely by the extent of and variability in throat deposition. We hypothesize that throat deposition is the major determinant for lung deposition of an inhaled aerosol, and its absolute variability will largely be determined by the absolute variability in throat deposition. The relative variability in lung deposition will therefore tend to be high for low lung deposition and low for high lung deposition. Consequently, low relative variability in lung deposition can only be attained if high lung deposition is achieved.

An in vivo and in vitro comparison of two powder inhalers following storage at hot/humid conditions.

Dry powder inhalers (DPIs) are increasingly being used for the treatment of asthma and COPD. A potential drawback is that DPIs can be sensitive to humidity. Two DPIs, Symbicort Turbuhaler and Seretide Diskus, were stored 3 months at either 25 degrees C/30% RH or 40 degrees C/75% RH. After storage, delivered, as well as fine particle dose, FPD, were tested in vitro and lung deposition, of the steroid components, was assessed in vivo. After storage at 40 degrees C/75% RH, delivered dose as well as FPD from Symbicort Turbuhaler was virtually unchanged while FPD for Seretide Diskus decreased by about 50% despite no decrease in delivered dose. For both products, no difference in FPD was seen after storage at 25 degrees C/30% RH. These in vitro findings were confirmed in the in vivo part of the study. Lung deposition for Symbicort Turbuhaler was unaffected by 40 degrees C/75% RH storage, while for Seretide Diskus it was reduced with about 50%. The study extends previous in vitro observations of impaired performance of Seretide Diskus and demonstrates that this translates into decreased drug delivery to the site of action. The clinical importance of this finding has not been studied but could result in undertreatment.

Dose delivery late in the breath can increase dry powder aerosol penetration into the lungs.

In addition to aerosol particle size and mode of inhalation, the time-point of dose delivery during inhalation may be an important factor governing the intrapulmonary distribution of aerosolized drug. To generate different intrapulmonary deposition patterns of a drug model aerosol, a device with the capability of delivering small amounts of technetium-99m-labeled lactose dry powder at pre-set time-points during inhalation was developed. A single dose of the radioaerosol was delivered after inhalation of 20% (A) or 70% (B) of the vital capacity inhaled through the device. Twelve healthy subjects were studied in a randomized crossover fashion. Planar gamma scintigraphy was carried out, and the penetration index, PI, defined as the ratio of peripheral to central lung zone deposition of radioactivity, was estimated. A significant increase in PI from 3.0 (A) to 3.7 (B) was observed with the change from early to late delivery of the dose (p < 0.01). No difference in the total amount of radioactivity within the lungs could be detected. In conclusion, independent of total pulmonary deposition, deeper dry powder aerosol penetration into the lungs was found for the dose delivered at near end instead of at the beginning of inhalation. By computational modeling of the aerosol transport and deposition, that finding was mechanistically explained by differences in airway caliber as a consequence of the level of lung inflation at the time-point of dose delivery.

Planar gamma scintigraphy--points to consider when quantifying pulmonary dry powder aerosol deposition.

Methodological aspects of planar gamma scintigraphy used to quantify pulmonary aerosol deposition were investigated using an experimental dry powder formulation. Particles of micronized salbutamol sulphate were labelled with technetium-99m and admixed to an ordered mixture of unlabelled micronized salbutamol sulphate and larger carrier particles of lactose. The radioaerosol was administered to 24 healthy subjects, 12 in each of two consecutive, similarly designed studies. Pulmonary deposition was determined using two methods: repeated planar imaging, and pharmacokinetic assessments following charcoal co-administration to prevent gastrointestinal salbutamol absorption. After due consideration had been taken to ensure appropriate radiolabelling, image acquisition and processing procedures, a scintigraphic estimate of 26.2% (with 95% confidence interval of 24.2-28.4%) was obtained, which did not significantly differ from the pharmacokinetic estimate of 26.4% (24.4-28.7%). In summary, pre-study validation of the radiolabelling technique, quality control of radioaerosols produced during the study, correction for re-distribution of radiolabel from the lungs, selection of regions of interest, assessment of lung contours, correction for tissue attenuation of gamma rays and establishment of the actual recovery of radioactivity in the scintigraphic measurements could potentially affect the accuracy of the scintigraphic estimate of pulmonary deposition and, thus, should be carefully considered in the design or evaluation of any such study.

Planar gamma scintigraphy--points to consider when quantifying pulmonary dry powder aerosol deposition.

Methodological aspects of planar gamma scintigraphy used to quantify pulmonary aerosol deposition were investigated using an experimental dry powder formulation. Particles of micronized salbutamol sulphate were labelled with technetium-99m and admixed to an ordered mixture of unlabelled micronized salbutamol sulphate and larger carrier particles of lactose. The radioaerosol was administered to 24 healthy subjects, 12 in each of two consecutive, similarly designed studies. Pulmonary deposition was determined using two methods: repeated planar imaging, and pharmacokinetic assessments following charcoal co-administration to prevent gastrointestinal salbutamol absorption. After due consideration had been taken to ensure appropriate radiolabelling, image acquisition and processing procedures, a scintigraphic estimate of 26.2% (24.2-28.4%) was obtained, which did not significantly differ from the pharmacokinetic estimate of 26.4% (24.4-28.7%). In summary, pre-study validation of the radiolabelling technique, quality control of radioaerosols produced during the study, correction for re-distribution of radiolabel from the lungs, selection of regions of interest, assessment of lung contours, correction for tissue attenuation of gamma rays and establishment of the actual recovery of radioactivity in the scintigraphic measurements could potentially affect the accuracy of the scintigraphic estimate of pulmonary deposition and, thus, should be carefully considered in the design or evaluation of any such study.

In vitro and in vivo aspects of quantifying intrapulmonary deposition of a dry powder radioaerosol.

Pulmonary delivery of pharmaceutical aerosols can be quantified using gamma scintigraphy. Technetium-99m, the most commonly used radionuclide in scintigraphic studies, cannot be incorporated into the drug molecule and, therefore, may be distributed differently from the drug itself, particularly if the drug is presented as a solid in a liquid suspension or as a dry powder formulation. This study demonstrated the importance of using conditions relevant to the in vivo situation in the in vitro characterisation of a dry powder aerosol of 99mTc-labelled lactose. The influence of inspiratory flow on the distribution of aerosol within the lungs was investigated in eight healthy subjects who inhaled the 99mTc-labelled lactose at four flows (30,40,60 and 80 l/min). No differences in penetration index (PI) or count density distribution of radioactivity were seen, indicating that regional distribution of aerosol in healthy airways was insensitive to differences in the inspiratory effort exerted by the subject while inhaling the experimental dry powder radioaerosol.