Mechanistic modeling of generic orally inhaled drug products: A workshop summary report.

In silico mechanistic modeling approaches have been designed by various stakeholders with the goal of supporting development and approval of generic orally inhaled drug products in the United States. This review summarizes the presentations and panel discussion that comprised a workshop session concentrated on the use of in silico models to predict various outcomes following orally inhaled drug product administration, including the status of such models and how model credibility may be effectively established.

Inhaled Medicines: Past, Present, and Future.

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include ß -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

On the Validation of Generational Lung Deposition Computer Models Using Planar Scintigraphic Images: The Case of Mimetikos Preludium.

Background: Mechanistic computer models for calculation of total and regional deposition of aerosols in the lungs are important tools for predicting or understanding clinical studies and for facilitating development of pharmaceutical inhalation products. Validation of such models must be indirect since generational in vivo data are lacking. Planar scintigraphy is probably the most common method addressing regional lung deposition in humans. Scintigraphic regions of interest (ROI) contain mixtures of airway generations and can therefore not be directly compared to model results. We propose a method to translate computed deposition per generation to deposition in scintigraphic ROI to be able to compare computed results with corresponding results obtained in humans. Methods: The total and regional lung deposition computed by the one-dimensional algebraic typical-path software Mimetikos Preludium was compared for 18 study legs in 14 published deposition studies involving 9 dry powder inhaler brands to the activity in planar scintigraphic ROIs (oropharyngeal, central [C], intermediate, and peripheral [P]) using for the computed regional lung distribution a generic mapping of the contribution of each airway generation to the ROIs. Results: The computed oropharyngeal and total lung deposition correlated with high significance (p < 0.0001) to the scintigraphic results with a near one-to-one relationship. For the regional lung distribution, computed C, P, and P/C results correlated with high significance (p < 0.01) to the corresponding scintigraphic measures. The computed C (P) deposition was on average about 28% lower (8% higher) than the mean scintigraphic results. The computed P/C ratio was on average 29% higher than the mean scintigraphic ratio. Conclusions: The results indicate that both the computational deposition model and the mapping algorithm are valid. The small underprediction of the C region merits further investigations. We believe that this method may prove useful also for the validation of computational fluid particle dynamic lung deposition models.

Pharmacokinetics of the Inhaled Selective Glucocorticoid Receptor Modulator AZD5423 Following Inhalation Using Different Devices.

AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility, developed for treatment of asthma and COPD. In this work, we aim to evaluate and compare the absorption pharmacokinetics (PK) of AZD5423 after inhalation via four devices, (Spira®, I-neb®, Turbuhaler® and a new dry powder inhaler (new DPI)) with two formulations using differently sized primary particles, and to compare the pulmonary bioavailability with the predicted lung deposited dose. Plasma concentration-time data after intravenous, oral and inhaled administration via four devices were available from two clinical studies in healthy and asthmatic subjects. A population PK modelling approach was taken to sequentially incorporate each route of administration, assuming parallel absorption compartments for inhaled AZD5423. A non-compartmental analysis for derivation of PK parameters was performed for comparison. Pulmonary bioavailability varied between devices, with the lowest estimates for I-neb (27%) and Turbuhaler (30%) and the highest for the new DPI (46%) and Spira (35-49%). The pulmonary bioavailability was substantially lower than the predicted lung deposited dose (range 59-90%). Lung absorption was separated into a faster and a slower process in the model. The half-life of the faster absorption appeared formulation-dependent, while the slower absorption (half-life of 0.59-0.78 h) appeared independent of formulation. The large difference in the estimated pulmonary bioavailability and the predicted lung deposited dose for AZD5423 implies an impact of mucociliary clearance. The lung absorption half-life indicates that AZD5423 is retained in the lung for a relatively short time.

Predicting Exposure After Oral Inhalation of the Selective Glucocorticoid Receptor Modulator, AZD5423, Based on Dose, Deposition Pattern, and Mechanistic Modeling of Pulmonary Disposition.

BACKGROUND: Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate. MATERIALS AND METHODS: A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions. Results from simulations were compared with observed pharmacokinetic data. RESULTS: Variations in systemic exposure (plasma concentration profile, AUC, and Cmax) resulting from variations in dose, deposition pattern, and dissolution rate could not be predicted solely from variations in delivered dose or predicted lung dose (as assessed using an anatomical mouth-throat model), suggesting incomplete pulmonary bioavailability. However, simulated systemic exposure well predicted observed systemic exposures for all tested formulations and devices. Furthermore, simulations of airway tissue exposure suggested that it was not directly linked to systemic exposure. CONCLUSIONS: Results support the initial hypothesis that systemic exposure of poorly soluble inhaled drugs is a complex but predictable function of dose, deposition pattern, and rate of dissolution. Furthermore, simulations indicate that local exposure for these types of drugs is not well correlated with systemic exposure. Hence, equivalence with respect to local exposure, and thus with respect to pharmacodynamic effect, cannot be fully inferred from systemic pharmacokinetic equivalence alone.

The leading hand in bimanual activities - A search for more valid handedness items.

SUMMARY: The aim of this pilot study is to test a new approach to handedness assessment based on the concept of the leading hand. A well-established graphomotor performance test of handedness (H-D-T) and a new test according on the concept of the leading hand were undertaken by 41 Viennese schoolchildren between 6 and 8 years of age. The new test is based on in vivo observations of bimanual activities. In detail the test battery consisted of 8 fine motor leading hand items. Participants had to open and close four small objects (one tube, three small bottles) in order to observe twisting movements and four small objects (2 matchboxes, 2 small brushes) in order to observe back-and-forth movements. It turned out that the leading hand does not correlate with the hand dominance in a graphomotor test to the degree that the handedness in unimanual items has been found to do and that right leading hand scores in bimanual items are encountered significantly less often than right hand scores in a graphomotor test. The findings of the present study suggest that tests of the leading hand in vivo may contribute to a higher validity of the assessment of handedness in examinations of the lateralization of higher cortical functions.

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.

In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols.

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.

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.

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.

Methodological modifications on quantification of phosphatidylethanol in blood from humans abusing alcohol, using high-performance liquid chromatography and evaporative light scattering detection.

BACKGROUND: Phosphatidylethanol (PEth) is an abnormal phospholipid formed slowly in cell membranes by a transphosphatidylation reaction from phosphatidylcholine in the presence of ethanol and catalyzed by the enzyme phospholipase D. PEth in blood is a promising new marker of ethanol abuse depending on the high specificity and sensitivity of this marker. None of the biological markers used in clinical routine at the present time are sensitive and specific enough for the diagnosis of alcohol abuse. The method for PEth analysis includes lipid extraction of whole blood, a one-hour HPLC separation of lipids and ELSD (evaporative light scattering) detection of PEth. RESULTS: Methodological improvements are presented which comprise a simpler extraction procedure, the use of phosphatidylbutanol as internal standard and a new algorithm for evaluation of unknown samples. It is further demonstrated that equal test results are obtained with blood collected in standard test tubes with EDTA as with the previously used heparinized test tubes. The PEth content in blood samples is stable for three weeks in the refrigerator. CONCLUSION: Methodological changes make the method more suitable for routine laboratory use, lower the limit of quantification (LOQ) and improve precision.

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.

Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: Design.

A new cascade impactor has been designed specifically for pharmaceutical inhaler testing. This impactor, called the Next Generation Pharmaceutical Impactor (NGI), has seven stages and is intended to operate at any inlet flow rate between 30 and 100 L/min. It spans a cut size (D50) range from 0.54-microm to 11.7-microm aerodynamic diameter at 30 L/min and 0.24 microm to 6.12 microm at 100 L/min. The aerodynamics of the impactor follow established scientific principles, giving confident particle size fractionation behavior over the design flow range. The NGI has several features to enhance its utility for inhaler testing. One such feature is that particles are deposited on collection cups that are held in a tray. This tray is removed from the impactor as a single unit, facilitating quick sample turn-around times if multiple trays are used. For accomplishing drug recovery, the user can add up to approximately 40 mL of an appropriate solvent directly to the cups. Another unique feature is a micro-orifice collector (MOC) that captures in a collection cup extremely small particles normally collected on the final filter in other impactors. The particles captured in the MOC cup can be analyzed in the same manner as the particles collected in the other impactor stage cups. The user-friendly features and the aerodynamic design principles together provide an impactor well suited to the needs of the inhaler testing community.