Multitask learning for predicting pulmonary absorption of chemicals.

Pulmonary absorption is an important route for drug delivery and chemical exposure. To streamline the chemical assessment process for the reduction of animal experiments, several animal-free models were developed for pulmonary absorption research. While Calu-3 and Caco-2 cells and their derived computational models were used in estimating pulmonary permeability, the ex vivo isolated perfused lung (IPL) models are considered more clinically relevant measurements. However, the IPL experiments are resource-consuming making it infeasible for the large-scale screening of potential inhaled toxicants and drugs. In silico models are desirable for estimating pulmonary absorption. This study presented a novel machine learning method that employed an extratrees-based multitask learning approach to predict the IPL absorption rate constant (kaIPL) of various chemicals. The shared permeability knowledge was extracted by simultaneously learning three relevant tasks of Caco-2 and Calu-3 cell permeability and IPL absorption rate. Seven informative physicochemical descriptors were identified. A rigorous evaluation of the developed prediction model showed good performance with a high correlation between predictions and observations (r = 0.84) in the independent test dataset. Two case studies of inhalation drugs and respiratory sensitizers revealed the potential application of this model, which may serve as a valuable tool for predicting pulmonary absorption of chemicals.

Spermine with Sodium Taurocholate Enhances Pulmonary Absorption of Macromolecules in Rats.

The improvement effect of the combined use of spermine (SPM), a polyamine, with sodium taurocholate (STC) on the pulmonary drug absorption was investigated utilizing poorly absorbable drugs with various molecular sizes in rats. The pulmonary absorption of rebamipide, a low molecular but poorly absorbable drug after oral administration, was significantly improved by the combined use of SPM with STC (SPM-STC formulation), while poly- L-lysine did not show a significant change in rebamipide absorption from the lungs. Furthermore, the safety of the SPM-STC formulation for the lungs was assessed in rats by the histopathological study and any local toxicity was not observed while poly-L-lysine, a typical chemical causing the toxicity for the epithelial cells, provided several histopathological changes. In addition, the SPM-STC formulation significantly improved the pulmonary absorption of fluorescein isothiocyanate dextran 4 (FD-4, Mw ca 4000) and interferon-α (IFN-α, Mw ca 25,000) as well. Our present results clearly indicated that the SPM-STC formulation significantly improved the pulmonary absorption of poorly absorbable small and large molecular drugs without any harmful effects on the lungs. Therefore, the SPM-STC formulation would be a useful one for the pulmonary absorption of drugs, specifically macromolecular ones, which are very difficult to be absorbed after oral administration.

Condiciones de trabajo asociadas a síntomas respiratorios por exposición a residuos de plaguicidas / Working conditions associated with respiratory symptoms due to exposure to pesticide residues

INTRODUCCIÓN. La exposición a plaguicidas de trabajadores agrícolas y productores ha sido causal de aparición de síntomas respiratorios teniendo el Ecuador el 62% de población rural dedicada a esta actividad. OBJETIVO. Identificar y evaluar las condiciones de trabajo asociadas a síntomas respiratorios por exposición a residuos de plaguicidas. MATERIALES Y MÉTODOS. Estudio analítico transversal. Población de 140 y muestra de 102 trabajadores de la empresa Condimensa. Los datos fueron recolectados mediante el cuestionario de salud respiratoria de la European Comunity Respiratory Health Survey en Latinoamérica segunda versión, en septiembre de 2020. RESULTADOS. Se encontró una relación estadísticamente significativa entre flema crónica y sexo con unA Prueba Exacta de Fisher (p=0,015), la manipulación de sustancias nocivas o toxicas (p=0,001), y la condición de exposición química (p=0,0006). Mediante análisis de regresión logística se determinó que la manipulación de sustancias nocivas o tóxicas (Odds Ratio 5.50, Intervalo de Confianza 95% 1.58 ­ 19.17), y estar expuesto a químicos (Odds Ratio 7.00, Intervalo de Confianza 95% 2.11 ­ 23.22), fueron factores de riesgo para el desarrollo de síntomas respiratorios: flema crónica, tos crónica, sibilancia, opresión en el pecho, disnea crónica, bronquitis crónica. CONCLUSIÓN. Se registró y evaluó las condiciones de trabajo asociadas a síntomas respiratorios por exposición a residuos; y, la evidencia fue fuerte para la exposición residual a plaguicidas.

INTRODUCTION.Worldwide Exposure to pesticides in agricultural workers and producers has been the cause of the appearance of respiratory symptoms. Ecuador having 62% of the rural population dedicated to this activity. OBJETIVE. Identify and evaluate the working conditions associated with respiratory symptoms due to exposure to pesticide residues. MATERIALS AND METHODS. Cross-sectional analytical study. Population of 140 and sample of 102 workers of the Condimensa company. The data were collected using the respiratory health questionnaire of the European Community Respiratory Health Survey in Latin America, second version, in september 2020. RESULTS. A statistically significant relationship between chronic phlegm and sex type was found with a Fisher exact (p=0,015), the handling of harmful or toxic substances Fisher exact (p = 0.001), and the condition of chemical exposure a Fisher Exact Test (p=0,0006). Through logistic regression analysis, it was determined that the handling of harmful or toxic substances (Odds Ratio 5.50, Confidence Interval 95% 1.58 - 19.17), and being exposed to chemicals (Odds Ratio 7.00, Confidence Interval 95% 2.11 - 23.22), were risk factors for the development of respiratory symptoms: chronic phlegm, chronic cough, wheezing, chest tightness, chronic dyspnea, chronic bronchitis. CONCLUSION. The working conditions associated with respiratory symptoms due to exposure to residues associated with chronic phlegm were recorded and evaluated; and the evidence was strong for residual pesticide exposure.

Mucociliary Clearance Differs in Mild Asthma by Levels of Type 2 Inflammation.

BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.

DSPE-PEG polymers for improving pulmonary absorption of poorly absorbed macromolecules in rats and relative mechanism.

OBJECTIVE: This study aims to investigate the potential of DSPE-PEG polymers (DSPE-PEG-OH and DSPE-PEG-SH) on improving absorption of poorly absorbable macromolecules via intrapulmonary administration and underlying mechanism. METHODS: In situ pulmonary absorption experiments were performed to investigate the absorption of model compounds after intrapulmonary administration to rats. The local membrane damage induced by these DSPE-PEG polymers were evaluated based on morphological observation of lung tissues and measurement of biological toxic markers in bronchoalveolar lavage fluid (BALF) postintrapulmonary delivery of DSPE-PEG polymers to rats. The underlying enhancement mechanism of these polymers was explored by investigating their effects on the pulmonary membrane fluidity and gene expression of tight junction associated proteins with fluorescence polarization and western blotting, respectively. RESULTS: Intrapulmonary delivery of these DSPE-PEG polymers significantly enhanced absorptions of poorly absorbed model drugs and did not induce serious damage to the pulmonary membranes of rats. Mechanistic studies demonstrated unaffected pulmonary membrane fluidity and up-regulated expression levels of tight junction-associated proteins by DSPE-PEG polymers, thus indicating that paracellular pathways might be included in the underlying mechanisms by which DSPE-PEG polymers exerted their enhancing actions on drug absorption. CONCLUSIONS: These findings suggested that these DSPE-PEG polymers are potential for promoting absorptions of poorly absorbable macromolecules with no evidence of damage to the local pulmonary membranes of rats.Novelty statementIn this study, DSPE-PEG-OH and DSPE-PEG-SH polymers, two DSPE-PEG2000 conjugates with different terminal groups demonstrated significant promoting effects on the absorption of poorly absorbed macromolecular drugs after intrapulmonary delivery to rats, and did not induce serious damage to the pulmonary membranes of rats. These DSPE-PEG polymers could statistically downregulate expression levels of tight junction-associated proteins (ZO-1 and occludin), indicating the underlying mechanism by which these polymers exerted their absorption enhancing actions through pulmonary epithelial paracellular pathways. Thus, this study exhibited prospective potential of these DSPE-PEG polymers in developing into dosage forms with the aim to improve the poor bioavailability of some poorly absorbed macromolecular drugs.

A transcriptomic overview of lung and liver changes one day after pulmonary exposure to graphene and graphene oxide.

Hazard evaluation of graphene-based materials (GBM) is still in its early stage and it is slowed by their large diversity in the physicochemical properties. This study explores transcriptomic differences in the lung and liver after pulmonary exposure to two GBM with similar physical properties, but different surface chemistry. Female C57BL/6 mice were exposed by a single intratracheal instillation of 0, 18, 54 or 162 µg/mouse of graphene oxide (GO) or reduced graphene oxide (rGO). Pulmonary and hepatic changes in the transcriptome were profiled to identify commonly and uniquely perturbed functions and pathways by GO and rGO. These changes were then related to previously analyzed toxicity endpoints. GO exposure induced more differentially expressed genes, affected more functions, and perturbed more pathways compared to rGO, both in lung and liver tissues. The largest differences were observed for the pulmonary innate immune response and acute phase response, and for hepatic lipid homeostasis, which were strongly induced after GO exposure. These changes collective indicate a potential for atherosclerotic changes after GO, but not rGO exposure. As GO and rGO are physically similar, the higher level of hydroxyl groups on the surface of GO is likely the main reason for the observed differences. GO exposure also uniquely induced changes in the transcriptome related to fibrosis, whereas both GBM induced similar changes related to Reactive Oxygen Species production and genotoxicity. The differences in transcriptomic responses between the two GBM types can be used to understand how physicochemical properties influence biological responses and enable hazard evaluation of GBM and hazard ranking of GO and rGO, both in relation to each other and to other nanomaterials.

Pulmonary drug absorption and systemic exposure in human: Predictions using physiologically based biopharmaceutics modeling.

Systemic exposure of inhaled drugs is used to estimate the local lung exposure and assess systemic side effects for drugs with local pharmacological targets. Predicting systemic exposure is therefore central for successful development of drugs intended to be inhaled. Currently, these predictions are based mainly on data from in vitro experiments, but the accuracy of these predictions might be improved if they were based on data with higher physiological relevance. In this study, systemic exposure was simulated by applying biopharmaceutics input parameters from isolated perfused rat lung (IPL) data to a lung model developed in MoBi® as an extension to the full physiologically-based pharmacokinetic (PBPK) model in PK-Sim®. These simulations were performed for a set of APIs with a variety of physicochemical properties and formulation types. Simulations based on rat IPL data were also compared to simulations based on in vitro data. The predictive performances of the simulations were evaluated by comparing simulated plasma concentration-time profiles to clinical observations after pulmonary administration. Simulations using IPL-based input parameters predicted systemic exposure well, with predicted AUCs within two-fold of the observed value for nine out of ten drug compounds/formulations, and predicted Cmax values within two-fold for eight out of ten drug compounds/formulations. Simulations using input parameters based on IPL data performed generally better than simulations based on in vitro input parameters. These results suggest that the developed model in combination with IPL data can be used to predict human lung absorption for compounds with different physicochemical properties and types of inhalation formulations.

Inter-compound and Intra-compound Global Sensitivity Analysis of a Physiological Model for Pulmonary Absorption of Inhaled Compounds.

In recent years, global sensitivity analysis (GSA) has gained interest in physiologically based pharmacokinetics (PBPK) modelling and simulation from pharmaceutical industry, regulatory authorities, and academia. With the case study of an in-house PBPK model for inhaled compounds in rats, the aim of this work is to show how GSA can contribute in PBPK model development and daily use. We identified two types of GSA that differ in the aims and, thus, in the parameter variability: inter-compound and intra-compound GSA. The inter-compound GSA aims to understand which are the parameters that mostly influence the variability of the metrics of interest in the whole space of the drugs' properties, and thus, it is useful during the model development. On the other hand, the intra-compound GSA aims to highlight how much the uncertainty associated with the parameters of a given drug impacts the uncertainty in the model prediction and so, it is useful during routine PBPK use. In this work, inter-compound GSA highlighted that dissolution- and formulation-related parameters were mostly important for the prediction of the fraction absorbed, while the permeability is the most important parameter for lung AUC and MRT. Intra-compound GSA highlighted that, for all the considered compounds, the permeability was one of the most important parameters for lung AUC, MRT and plasma MRT, while the extraction ratio and the dose for the plasma AUC. GSA is a crucial instrument for the quality assessment of model-based inference; for this reason, we suggest its use during both PBPK model development and use.

Is adipose tissue suitable for detection of (synthetic) cannabinoids? A comparative study analyzing antemortem and postmortem specimens following pulmonary administration of JWH-210, RCS-4, as well as ∆9-tetrahydrocannabinol to pigs.

Examining fatal poisonings, chronic exposure may be reflected by the concentration in tissues known for long-term storage of drugs. Δ9-tetrahydrocannabinol (THC) persists in adipose tissue (AT), but sparse data on synthetic cannabinoids (SC) are available. Thus, a controlled pig study evaluating antemortem (AM) disposition and postmortem (PM) concentration changes of the SC 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210) and 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4) as well as THC in AT was performed. The drugs were administered pulmonarily (200 µg/kg body weight) to twelve pigs. Subcutaneous (s.c.) AT specimens were collected after 15 and 30 min and then hourly up to 8 h. At the end, pigs were sacrificed and s.c., perirenal, and dorsal AT specimens were collected. The carcasses were stored at room temperature (RT; n = 6) or 4 °C (n = 6) and specimens were collected after 24, 48, and 72 h. After homogenization in acetonitrile and standard addition, LC-MS/MS was performed. Maximum concentrations were reached 0.5-2 h after administration amounting to 21 ± 13 ng/g (JWH-210), 24 ± 13 ng/g (RCS-4), and 22 ± 20 ng/g (THC) and stayed at a plateau level. Regarding the metabolites, very low concentrations of N-hydroxypentyl-RCS-4 (HO-RCS-4) were detected from 0.5 to 8 h. PM concentrations of parent compounds did not change significantly (p > 0.05) over time under both storage conditions. Concentrations of HO-RCS-4 significantly (p < 0.05) increased in perirenal AT during storage at RT. These results suggest a rapid distribution and persistence in s.c. AT. Furthermore, AT might be resistant to PM redistribution of parent compounds. However, significant PM increases of metabolite concentrations might be considered in perirenal AT.

Transport properties in CFTR-/- knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption.

Previous analysis of CFTR-knockout (CFTR-/-) in piglets has provided important insights into the pathology of cystic fibrosis. However, controversies exist as to the true contribution of CFTR to the pH balance in airways and intestine. We therefore compared ion transport properties in newborn wild-type (CFTR+/+) and CFTR-knockout (CFTR-/- piglets). Tracheas of CFTR-/- piglets demonstrated typical cartilage malformations and muscle cell bundles. CFTR-/- airway epithelial cells showed enhanced lipid peroxidation, suggesting inflammation early in life. CFTR was mainly expressed in airway submucosal glands and was absent in lungs of CFTR-/- piglets, while expression of TMEM16A was uncompromised. mRNA levels for TMEM16A, TMEM16F, and αßγENaC were unchanged in CFTR-/- airways, while mRNA for SLC26A9 appeared reduced. CFTR was undetectable in epithelial cells of CFTR-/- airways and intestine. Small intestinal epithelium of CFTR-/- piglets showed mucus accumulation. Secretion of both electrolytes and mucus was activated by stimulation with prostaglandin E2 and ATP in the intestine of CFTR+/+, but not of CFTR-/- animals. pH was measured inside small bronchi using a pH microelectrode and revealed no difference between CFTR+/+ and CFTR-/- piglets. Intracellular pH in porcine airway epithelial cells revealed only a small contribution of CFTR to bicarbonate secretion, which was absent in cells from CFTR-/- piglets. In contrast to earlier reports, our data suggest a minor impact of CFTR on ASL pH. In contrast, enhanced amiloride-sensitive Na+ absorption may contribute to lung pathology in CFTR-/- piglets, along with a compromised CFTR- and TMEM16A-dependent Cl- transport.

The Role of MicroRNA in the Airway Surface Liquid Homeostasis.

Mucociliary clearance, mediated by a coordinated function of cilia bathing in the airway surface liquid (ASL) on the surface of airway epithelium, protects the host from inhaled pathogens and is an essential component of the innate immunity. ASL is composed of the superficial mucus layer and the deeper periciliary liquid. Ion channels, transporters, and pumps coordinate the transcellular and paracellular movement of ions and water to maintain the ASL volume and mucus hydration. microRNA (miRNA) is a class of non-coding, short single-stranded RNA regulating gene expression by post-transcriptional mechanisms. miRNAs have been increasingly recognized as essential regulators of ion channels and transporters responsible for ASL homeostasis. miRNAs also influence the airway host defense. We summarize the most up-to-date information on the role of miRNAs in ASL homeostasis and host-pathogen interactions in the airway and discuss concepts for miRNA-directed therapy.

Non-intrusive high resolution in-vitro measurement of regional drug powder deposition.

Optical Coherence Tomography (OCT) is a high-resolution and non-invasive cross-sectional imaging technique mainly used for medical imaging and industrial non-destructive testing. However, its feasibility in the quantification of pulmonary drug deposition has not been investigated. In this study, an optically accessible airway model of the upper airway and the tracheobronchial tree was used, and experiments were performed at flow rates of 40 L/min, 60 L/min and 80 L/min. Drug deposition in different regions of the airway cast has been determined and quantified from OCT images of the deposition layer. Regionally resolved measurement of deposition shows that flow rate has a significant effect (p = 0.04) on the average thickness of the deposition layer in the upper airway but not in the tracheobronchial tree under these test conditions. These localized and high-resolution measurements of deposition also demonstrate that the flow rate can influence the spatial uniformity of the deposition layer. The technique is able to provide significant regional drug deposition details, including the thickness, spatial deposition pattern and micro-cavities in the deposition layer, that would potentially serve to assess the efficacy of inhalation drug delivery systems.

Efficacy of SPM-NONOate following intrapulmonary delivery in promoting absorptions of poorly absorbed macromolecules in rats and the underling mechanism.

This research aims to investigate the potential of N-[4-[1-(3-Aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl]-1,3-propanediamine (SPM-NONOate) for promoting the absorption of poorly absorbed macromolecules delivered by intrapulmonary route. Influence of SPM-NONOate on the drug absorption was characterized by using a series of fluorescein isothiocyanate-labeled dextrans (FDs) as affordable models of hydrophilic macromolecules with established tools for quantitative analysis. SPM-NONOate increased concentration-dependently within 1-10 mM the pulmonary absorptions of FDs in rats. Moreover, this promoting effect varied with the molecular weight of FDs, and the largest absorption enhancement effect was obtained for FD70. SPM-NONOate also showed promising enhancement potential on the absorption of some therapeutic peptides, where obvious hypoglycemic and hypocalcemic effects were observed after intrapulmonary delivery of insulin and calcitionin, respectively, with SPM-NONOate to rats. The safety of SPM-NONOate was confirmed based on measurement of some biological markers in bronchoalveolar lavage fluid (BALF) of rats. Additionally, mechanism underling the absorption enhancement action of SPM-NONOate was explored by combinatorial administration of FD4 and SPM-NONOate with various scavengers and generator to rat lungs. Results indicated that NO released from SPM-NONOate induced the enhancement in the drug absorption, and peroxynitrate, a NO metabolite, possibly participated in the absorption enhancing action of SPM-NONOate.

Caproyl-Modified G2 PAMAM Dendrimer (G2-AC) Nanocomplexes Increases the Pulmonary Absorption of Insulin.

We aimed to investigate the absorption-enhancing effect (AEE) of caproyl-modified G2 PAMAM dendrimer (G2-AC) on peptide and protein drugs via the pulmonary route. In this study, G2 PAMAM dendrimer conjugates modified with caproic acid was synthesized, the pulmonary absorption of insulin as models with or without G2-AC were evaluated. The results indicated that G2-AC6 exhibited a greatest AEE for insulin in various caproylation levels of G2-AC. G2-AC6 could significantly enhance the absorption of insulin, and the AEE of G2-AC6 was concentration-dependent. In toxicity tests, G2-AC6 displayed no measurable cytotoxicity to the pulmonary membranes over a concentration range from 0.1% (w/v) to 1.0% (w/v). Measurements of the TEER and permeability showed that G2-AC6 significantly reduced the TEER value of CF and increased its Papp value. The results suggested that G2-AC6 could cross epithelial cells by means of a combination of paracellular and transcellular pathways. These findings suggested G2-AC6 at lower concentrations (below 1.0%, w/v) might be promising absorption enhancers for increasing the pulmonary absorption of peptide and protein drugs.

Nicotine absorption during electronic cigarette use among regular users.

BACKGROUND: The capability of electronic cigarette devices (e-cigs) to deliver nicotine is key to their potential to replace combustible cigarettes. We compared nicotine delivery and subjective effects associated with the use of two classes of e-cigarettes and cigarettes. METHODS: 14 e-cigarette users were instructed to vape their own e-cigarette device every 20 seconds for 10 minutes while blood was drawn at 1, 2, 4, 6, 8, 10,12, and 15 minutes after initiating vaping. Users rated withdrawal symptoms and side effects before and after vaping. E-cigarette devices were classified as first-generation (same size as cigarette, no activation button) or advanced (larger than cigarette with an activation button). Separately, 10 cigarette smokers completed a similar protocol. Fisher's Exact Test and two-sided t-tests were used as appropriate to determine differences in outcomes between first-generation e-cigarette users, advanced e-cigarette users, and smokers. RESULTS: Compared to first-generation devices, advanced devices were associated with greater serum nicotine Cmax (ng/ml) (11.5 v. 2.8, p = 0.0231) and greater nicotine boost (ng/ml) (10.8 v. 1.8, p = 0.0177). Overall, e-cigarettes users experienced a significant reduction in withdrawal and craving, although there were no significant differences between users of first-generation and advanced devices. Comparing e-cigarettes overall to cigarettes, cigarettes were associated with greater Cmax (25.9 v. 9.0, p = 0.0043) and greater nicotine boost (21.0 v. 8.2, p = 0.0128). CONCLUSIONS: Advanced e-cigarettes delivered significantly more nicotine than first-generation devices but less than combustible cigarettes. Overall, e-cigarette use was associated with a reduction in withdrawal and craving with no reported side effects. The wide variation in nicotine absorption from different e-cigarette devices should be considered in studies of e-cigarettes for smoking cessation.

Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model.

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused rat lung (IPL) model. Two particle size distributions (d50 = 1.2 µm and d50 = 2.8 µm) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter ( kex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter ( kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 µM), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 µm). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between kex vivo and kin vitro. The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms.

BACKGROUND: Predicting local lung tissue pharmacodynamic (PD) responses of inhaled drugs is a longstanding challenge related to the lack of experimental techniques to determine local free drug concentrations. This has prompted the use of physiologically based pharmacokinetic (PBPK) modeling to potentially predict local concentration and response. A unique opportunity for PBPK model evaluation is provided by the clinical PD data for salbutamol, which in its inhaled dosage form (400 µg), produces a higher bronchodilatory effect than in its oral dosage form (2 mg) despite lower drug concentrations in blood. The present study aimed at evaluating whether inhalation PBPK model predictions of free drug in tissue would be predictive of these observations. METHODS: A PBPK model, including 24 airway generations, was parameterized to describe lung, plasma, and epithelial lining fluid concentrations of salbutamol administered intratracheally and intravenously to rats (100 nmol/kg). Plasma and lung tissue concentrations of unbound (R)-salbutamol, the active enantiomer, were predicted with a humanized version of the model and related to effect in terms of forced expiratory volume in 1 second (FEV1). RESULTS: In contrast to oral dosing, the model predicted inhalation to result in spatial heterogeneity in the target site concentrations (subepithelium) with higher free drug concentrations in the lung as compared with the plasma. FEV1 of inhaled salbutamol was accurately predicted from the PK/PD relationship derived from oral salbutamol and PBPK predictions of free concentration in airway tissue of high resistance (e.g., 6th generation). CONCLUSION: An inhalation PBPK-PD model was developed and shown predictive of local pharmacology of inhaled salbutamol, thus conceptually demonstrating the validity of PBPK model predictions of free drug concentrations in lung tissue. This achievement unlocks the power of inhalation PBPK modeling to interrogate local pharmacology and guide optimization and development of inhaled drugs and their formulations.

Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis.

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.