Jérôme Montharu

Aerosol Deposition in Neonatal Ventilation

Lung deposition of inhaled drugs in ventilated neonates has been studied in models of questionable relevance. With conventional nebulizers, pulmonary deposition has been limited to 1% of the total dose. The objective of this study was to assess lung delivery of aerosols in a model of neonatal ventilation using a conventional and novel electronic micropump nebulizer. Aerosol deposition studies with 99mTc diethylenetriamine pentaacetate (99mTc-DTPA) were performed in four macaques (2.6 kg) that were ventilated through a 3.0-mm endotracheal tube (with neonatal settings (peak inspiratory pressure 12–14 mbar, positive end-expiratory pressure 2 mbar, I/E ratio 1/2, respiratory rate 40/min), comparing a jet-nebulizer MistyNeb (3-mL charge, 4.8 μm), an electronic micropump nebulizer operating continuously [Aeroneb Professional Nebulizer (APN-C); 0.5-mL charge, 4.6 μm], and another synchronized with inspiration [Aeroneb Professional Nebulizer Synchronized (APN-S); 0.5-mL charge, 2.8 μm]. The amount of radioactivity deposited into lungs and connections and remaining in the nebulizer was measured by a gamma counter. Despite similar amounts of 99mTc-DTPA in the respiratory circuit with all nebulizers, both APN-S and APN-C delivered more drug to the lungs than MistyNeb (14.0, 12.6, and 0.5% in terms of percentage of nebulizer charge, respectively; p = 0.006). Duration of delivery was shorter with APN-C than with the two other nebulizers (2 versus 6 and 10 min for the APN-S and the MistyNeb, respectively; p < 0.001). Electronic micropump nebulizers are more efficient to administer aerosols in an animal model of ventilated neonates. Availability of Aerogens electronic micropump nebulizers offers new opportunities to study clinical efficacy and risks of aerosol therapy in ventilated neonates.

Disposable versus reusable jet nebulizers for cystic fibrosis treatment with tobramycin.

BACKGROUND Jet nebulizers are commonly used to administer aerosolized tobramycin to CF patients. The aim of this study was to assess the performance of disposable jet nebulizers as an alternative to reusable nebulizers such as the Pari LC Plus. METHOD From a survey conducted in 49 CF centers in France, 18 disposable jet nebulizer systems were selected. An in vitro study was performed with 20 jet nebulizer/air source combinations (18 disposable and 2 reusable) to determine their performance with tobramycin solution (300 mg/5 mL). A scintigraphic deposition study in baboons was performed to validate the in vitro data. RESULTS In vitro and in vivo results correlated. There was no overall relationship between the compressed air source and nebulizer performance, but the nebulizer interface was responsible for significantly different results. CONCLUSIONS None of the disposable nebulizers tested in this study can be recommended as an alternative to the Pari LC Plus nebulizer for tobramycin.

Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system.

Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream.

Evaluation of lung tolerance of ethanol, propylene glycol, and sorbitan monooleate as solvents in medical aerosols.

BACKGROUND Aerosol therapy is an expanding technique allowing administration of drugs acting locally in the bronchial tree and lungs or acting systemically after absorption through the respiratory tract. However, the choice of solvents and adjuvants is a critical step in the formulation process of new drugs. Pulmonary tolerance of ethanol, propylene glycol and sorbitan ester was evaluated in a rat model of intratracheal administration using a Microsprayer in a 4-day toxicity study. METHODS Four groups of Sprague-Dawley rats (11 rats per group, n = 44) have received, on 4 consecutive days 150 microL of solutions containing the solvents, by intratracheal route using a IA-1B-2 inches-Microsprayer (PennCentury, Philadelphia, PA). Once a day, the rats received deionized water (control) or ethanol 10% or propylene glycol 30% or sorbitan monooleate 10%. All rats were sacrificed 24 h after the fourth administration. Biochemical analysis on bronchoalveolar lavage (BAL) fluid was performed on seven rats per group. The respiratory tract of the remaining four rats/group was examined histologically. RESULTS Biochemistry and histopathology findings demonstrated that under the conditions tested, deionized water, 10% ethanol, and 30% propylene glycol were tolerated in a qualitatively similar way presenting limited cellular reaction. In contrast, 10% sorbitan monooleate produced an accumulation of foamy macrophages in the lungs and a higher degree of inflammation. In addition, animals in this group showed higher polymorphonuclear neutrophil recruitment and total proteins levels in BAL fluid. CONCLUSION The overall results recommended ranking the vehicles according to the degree of inflammation which was induced: deionized water <10% ethanol < or =30% propylene glycol <10% Tween 80.

Particle Deposition in a Child Respiratory Tract Model: In Vivo Regional Deposition of Fine and Ultrafine Aerosols in Baboons

To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols ([d16–d84], equal to [0.15 µm–0.5 µm], [0.25 µm–1 µm], or [1 µm–9 µm]). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 µm–9 µm] aerosol (72%±17%). The [0.15 µm–0.5 µm] aerosol was associated almost exclusively with thoracic region deposition (84%±4%). Airborne particles in the range of [0.25 µm–1 µm] showed an intermediate deposition pattern, with 49%±8% in the extrathoracic region and 51%±8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 µm–9 µm] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.

VEGF neutralizing aerosol therapy in primary pulmonary adenocarcinoma with K-ras activating-mutations

K-ras mutations promote angiogenesis in lung cancer and contribute to the drug resistance of cancer cells. It is not clear whether K-ras mutated adenocarcinomas are sensitive to anti-angiogenic therapy with monoclonal antibodies (mAbs) that target vascular endothelial growth factor (VEGF). Anti-angiogenic mAbs are usually delivered systemically, but only a small proportion reaches the lung after intravenous injection. We investigated the relevance of a non-invasive pulmonary route for the delivery of anti-VEGF mAbs in the mouse K-rasLA1 model. We found that pulmonary delivery of these mAbs significantly reduced the number of tumor lesions and inhibited malignant progression. The antitumor effect involves the VEGFR2-dependent inhibition of blood vessel growth, which impairs tumor proliferation. Pharmacokinetic analysis of aerosolized anti-VEGF showed its low rate of passage into the bloodstream, suggesting that this delivery route is associated with reduced systemic side effects. Our findings highlight the value of the aerosol route for administration of anti-angiogenic mAbs in pulmonary adenocarcinoma with K-ras activating-mutations.

Lung Deposition of HFA Beclomethasone Dipropionate in an Animal Model of Bronchopulmonary Dysplasia

The best delivery of a drug in ventilated neonates is obtained when using a small particle diameter solution administered via a spacer. Lung deposition of hydrofluoroalkane beclomethasone dipropionate (QVAR, 1.3 μm particles), delivered via an Aerochamber-MV15, was measured in piglets under conditions mimicking ventilated severely ill neonates (uncuffed 2.5 mm endotracheal tube; peak pressure 16 cm H2O; respiratory rate 40/min). After determining the mass and particle size distribution of the 99mTc-labeled and unlabeled drug, three lung deposition studies were performed: after 1 h of ventilation (controls, n = 18), after 48 h aggressive ventilation inducing an acute lung injury (nine piglets out of the controls), and after increasing the pressure to 24 cm H2O during drug delivery (five piglets out of the nine with acute lung injury). All piglets were then killed for lung histology. Results (median, range), expressed as a percentage of the delivered dose, were compared using an inferential or the Friedman test. While lung deposition was low, it was greater (p = 0.003) in controls (2.66%, 0.50–7.70) than in piglets with histologically confirmed acute lung injury (0.26%, 0.06–1.28) or under a high-pressure ventilation (1.01%, 0.30–2.15). Lung deposition of QVAR in an animal model of ventilated neonates is low, variable, and dramatically affected by lung injury.

Lung and Serum Teicoplanin Concentration After Aerosol and Intravenous Administration in a Rat Model

BACKGROUND Ventilator-associated pneumonia (VAP) caused by methicillin-resistant Staphylococcus aureus is a major cause of mortality in mechanically ventilated patients. Nebulization of teicoplanin is an alternative way of administration that may provide higher lung tissue concentrations than intravenous (IV) delivery. The aim of this study was to compare the administration of teicoplanin via aerosol with the IV route by measuring the lung and the serum teicoplanin concentrations in a rat model. METHODS Eighty healthy male Sprague-Dawley rats were anesthetized and received a single dose of teicoplanin by the IV or aerosol route. After sacrifice, lung and blood samples were collected and teicoplanin concentrations were measured with fluorescence polarization. A noncompartmental approach was used. The area under the concentration curve/minimal inhibition concentration ratio (AUC/MIC), AUC, absorbed fraction, mean residence time (MRT), and mean absorption time (MAT) of teicoplanin were calculated. RESULTS Mean±SD lung tissue concentrations of teicoplanin in the aerosol group were significantly higher than those in the IV group (p<0.0001). The mean lung tissue concentration achieved at 15 min was 1.94±1.33 mg/g in the aerosol group and 0.04±0.01 mg/g in the IV group. The mean AUClung was 67.4 mg hr(-1)g(-1) after aerosol and 0.8 mg hr(-1)g(-1) after the IV route. In the aerosol group, AUCserum/MIC ratio was 605/2, and in the IV route, AUCserum/MIC ratio was 682/2. MAT was longer after aerosol than after the IV route (0.91 hr versus 0.06 hr), and MRT was longer after aerosol than after IV bolus administration (6.52 hr versus 5.61 hr). CONCLUSION Teicoplanin concentrations in the lung tissue of the rat model were significantly higher by the aerosol route than by the IV route. The AUClung after nebulization was 84 times higher than delivery by the IV route, and the AUClung/MIC ratio after nebulization met the recommended target to eradicate Staphylococcus aureus. Administration of teicoplanin by the aerosol route could represent one of the new therapeutic weapons of the treatment of the VAP.