Pharmacokinetics of high-dose nebulized amikacin in ventilated critically ill patients.

BACKGROUND: Antibiotic nebulization theoretically allows the delivery of high doses to the lungs together with limited systemic exposure and toxicity. This study aimed to describe amikacin pharmacokinetics, and especially its absorption, in patients treated with high-dose nebulized amikacin. PATIENTS AND METHODS: Twenty critically ill patients experiencing ventilator-associated pneumonia received a 20 mg/kg infusion of amikacin, followed by either three other infusions or three nebulizations of 60 mg/kg amikacin. An extensive sampling regimen allowed measurement of amikacin serum concentrations at 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 h after each administration. Amikacin pharmacokinetics was studied by population compartmental modelling. RESULTS: Amikacin pharmacokinetics was best described using a two-compartment structural model with first-order distribution and elimination, in which lung absorption was described using a transit model. Estimated means (interindividual variability) of the main parameters were: bioavailability F = 2.65% (22.1%); transit compartments n = 1.58 (fixed); transit constant ktr = 1.38 h-1 (33.4%); central volume Vc = 10.2 L (10.5%); and elimination constant k10 = 0.488 h-1 (35.8%). The addition of interoccasion variability on F (44.0%) and k10 (41.7%) allowed the description of intraindividual variability of bioavailability and elimination. Amikacin clearance was positively correlated with baseline creatinine clearance. CONCLUSIONS: Our pharmacokinetic model provided an accurate description of amikacin concentrations following nebulization. There was wide interindividual and interoccasion variability in the absorption and elimination of amikacin. Nevertheless, systemic exposure after nebulization was always much lower than after infusion, an observation suggesting that nebulized high doses are safe in this regard and may be used to treat ventilator-associated pneumonia.

In vitro - in vivo correlation of intranasal drug deposition.

In vitro - in vivo correlation (IVIVC) allows prediction of in vivo drug deposition from a nasally inhaled drug based on in vitro drug measurements. In vitro measurements include physical particle characterization and, more recently, deposition studies using anatomical models. Currently, there is a lack of IVIVC for deposition measurements in anatomical models, especially for deposition patterns in various nasal cavity regions. Therefore, improvement of in vitro and in vivo measurement methods and knowledge about nasal deposition mechanisms should help IVIVC in the future.

[Good practice for aerosol therapy by nebulization in 2020]. / Bonnes pratiques de l'aérosolthérapie par nébulisation en 2020.

Nebulization is a drug delivery mode whose prescription and application remain uncertain. A guide to good practice has been proposed by the work group on aerosol therapy of the French Society for Respiratory Diseases, so-called GAT. The previous recommendations date from 2007. In addition to an update of data on nebulization, these expert recommendations aim to be of real help to the prescriber.

[Aerosols during mechanical ventilation]. / Aérosols en ventilation mécanique chez l'adulte.

Inhaled therapy is routinely employed during mechanical ventilation. Several factors affect aerosol delivery: the aerosol device, particle size, ventilator parameters, ventilator circuit and hygrometry. Non invasive ventilation is commonly used for treatment of exacerbations of chronic obstructive pulmonary disease. However, there are few data concerning the factors affecting aerosol delivery during this mode of ventilation. Optimal aerosol delivery during mechanical ventilation depends on the aerosol device, the respirator circuit and settings, and the patient himself.

[Environmental exposure chambers (EEC): A novel tool for pathophysiological and pharmaceutical research]. / Les chambres d'exposition environnementale (CEE) : un nouvel outil dans la recherche académique et industrielle.

Airborne allergic diseases (allergic asthma, rhinitis and conjunctivitis) have reached epidemic proportions and are a great burden for both society and individuals. Therefore we need to better understand the physiopathological mechanisms and to increase clinical research in these diseases. However, traditional outpatient studies are difficult and have number of limitations, in particular the variability of allergen exposure. Yet allergen provocation tests, especially bronchial challenges in asthma, are excellent tools to measure the efficiency of anti-allergic therapies. Environmental exposure chambers (EEC) allow the performance of controlled allergen provocation tests on a large scale with remarkable sensitivity, specificity and reproducibility. Moreover, they allow a precise collection of allergic symptoms, making them interesting tools for patho-physiological and clinical studies. During the last thirty years, they have assisted the study of anti-allergic therapies and provided data on their pharmacodynamic characteristics, particularly in allergic rhinitis. However, there are still no EEC tests centered on asthma. The EEC of Strasbourg (ALYATEC®) was developed to fulfill two objectives: to allow standardized allergenic and non-allergenic exposures with better control of the parameters than in other EEC and to offer a place to study asthma and anti-asthmatic therapies safely.

Insights on animal models to investigate inhalation therapy: Relevance for biotherapeutics.

Acute and chronic respiratory diseases account for major causes of illness and deaths worldwide. Recent developments of biotherapeutics opened a new era in the treatment and management of patients with respiratory diseases. When considering the delivery of therapeutics, the inhaled route offers great promises with a direct, non-invasive access to the diseased organ and has already proven efficient for several molecules. To assist in the future development of inhaled biotherapeutics, experimental models are crucial to assess lung deposition, pharmacokinetics, pharmacodynamics and safety. This review describes the animal models used in pulmonary research for aerosol drug delivery, highlighting their advantages and limitations for inhaled biologics. Overall, non-clinical species must be selected with relevant scientific arguments while taking into account their complexities and interspecies differences, to help in the development of inhaled medicines and ensure their successful transposition in the clinics.

[Aerosol: present and future]. / Aérosols: présent et futur.

INTRODUCTION: Aerosols, these particles considered initially like "magic", are slowly delivering their secrets. STATE OF ART: For several years studies on the subject have increased and companies have maximised their efforts to improve the technology for transforming drugs into the optimal aerosol. Recently new systems have appeared on the market. Mesh nebulisers can reduce the inhalation time, metered dose inhalers have modified their formulations to improve the efficiency of drug deposition and dry powder inhalers require lower inspiratory flows. PERSPECTIVES/CONCLUSIONS: In the near future new systems using technologies of greater or lesser sophistication should appear on the market.

Comparative analysis of different scintigraphic approaches to assess pulmonary ventilation.

A study was carried out to investigate the predictive value of 81-metastable-krypton (81mKr) distribution, high-size 99-metastable-technetium (99mTc) aerosol deposition and low-size 99mTc aerosol (Technegas) deposition on the pulmonary ventilation evaluated by 133-xenon (133Xe) lung scintigraphy, and to assess the correlation between the 81mKr distribution, the 99mTc aerosols deposition, and the respiratory parameters of patients with chronic obstructive pulmonary disease (COPD). Twenty COPD patients were included. The 81mKr, 133Xe, and 99mTc aerosol lung scintigraphies were successively carried out. The 81mKr distribution and 99mTc deposition were compared to the 133Xe distribution at equilibrium and to the 133Xe clearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81mKr and Technegas lung scintigraphies to detect alterations in ventilation revealed by 133Xe were defined. The 81mKr distribution and 99mTc deposition according to respiratory parameters were described using a principal component analysis. Compared to 133Xe distribution, a significantly higher distribution of 81mKr in the upper parts of the lungs in the more severe patients (p = 0.05), a significantly higher deposition of Technegas in the lower parts of the lungs (p = 0.0008), and a significantly higher deposition in the central parts of the high-size 99mTc aerosol were observed (p = 0.0001). The PPV and the NPV were, respectively, 0.54 and 0.58 for 81mKr and 0.54 and 0.55 for Technegas. There was a significant negative correlation between 81mKr distribution and 133Xe clearance (p = 0.0001) between Technegas deposition and 133Xe clearance (p = 0.0007), and between 99mTc diethylene-triamino-penta-acetate (DTPA) deposition and 133Xe clearance (p = 0.001). Both the 81mKr peripheral distribution and Technegas peripheral deposition correlated negatively with increased obstruction, as measured by forced expiratory volume in 1 sec (FEV1). Peripheral deposition of the high-size 99mTc aerosol deposition correlated with the inspiration/expiration time ratio. In conclusion, 81mKr and 99mTc aerosols' lung scintigraphies do not reflect exactly the pulmonary ventilation as measured by 133Xe scintigraphy.

[Critical evaluation of inhalation spacer devices available in France]. / Évaluation critique des chambres d'inhalation commercialisées en France.

OBJECTIVE: To identify the spacer devices sold in France and to provide a critical evaluation in the light of the published data. MATERIALS AND METHODS: We contacted the pharmaceutical companies, manufacturers and distributors of each spacer in order to obtain their technical parameters and the results of any in vitro or in vivo studies. A review of the literature via PubMed completed the first set of data. We were interested in the quantity of fine particles (less than 5 µm diameter) obtained with a cascade impactor at paediatric flow rates, for all inhaled drugs available in France. RESULTS: Eleven spacer devices were available in 2013 in France (Ablespacer®, Aerochamber Plus®, Babyhaler®, VHC Arrow®, L'Espace®, Funhaler®, Inhaler®, Itinhaler®, OptiChamber Diamond®, Tipshaler® and Vortex®), but three are no longer manufactured (Babyhaler®, Funhaler® and Inhaler®). All were small volume spacers, sold with facial masks of several different sizes. Four were antistatic (Aerochamber Plus®, Intinhaler®, OptiChamber Diamond® and Vortex®). Only salbutamol was tested with all the devices. Inhaled corticosteroids were tested with some and combinations were studied only with Ablespacer®, Aerochamber Plus®, Itinhaler®, and Vortex®. The results were difficult to interpret because the studies were conducted with very different protocols. The only clinical studies were conducted with Aerochamber Plus®, L'Espace® and Vortex®. CONCLUSION: There was a great disparity between commercialized spacer devices in terms of the available data describing their in vitro performance.

[Inhaled treatments: Choice of devices, systemic absorption of inhaled drugs and bitter taste receptors in the respiratory tract]. / Traitements inhalés : critères de choix des dispositifs, absorption systémique des médicaments par voie inhalée et récepteurs pulmonaires à l'amertume.

Inhaled drugs are now routinely prescribed in daily medical practice. Recent topics about these treatments have been developed during the fourth annual meeting of the Groupe de travail aérosolthérapie (GAT) of the French-speaking respiratory society (Société de pneumologie de langue française). This article focuses mainly upon the choice of devices, systemic absorption of inhaled drugs and bitter taste receptors in the respiratory tract, a potential new target for drug development.

Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis.

The purpose of this study was to define nebulization conditions providing delivery of aerosols of EPI-hNE4, an inhibitor of human neutrophil elastase (HNE). EPI-hNE4 was nebulized with Pari LC Star and tested at three concentrations (2.5, 5, and 10 mg/mL). The inhaled mass was measured over 15 min. Particle size distribution was measured by cascade impaction. The effect was also tested of mixing EPI-hNE4 with a (99m)Tc human serum albumin (HSA) tracer on the aerodynamic properties of the aerosol. The inhibitory activity of EPI-hNE4 after nebulization was assessed on purified HNE. The inhaled mass was 32.3 +/- 3.5% (mean +/- SD) after 10 min and 44.2 +/- 3.8% (mean +/- SD) after 15 min. Mass median aerodynamic diameter ranged between 1.2 and 1.8 microm. The (99m)Tc HSA EPI-hNE4 aerosol was similar in terms of particle size distribution (y = 1.0338x - 0.003, r = 0.83). (99m)Tc activity was predictive of EPI-hNE4 mass distribution (y = 1.0278x - 1.6991, r = 0.89). The inhibitory capacity of aerosolized samples remained unchanged after up to 10 min of nebulization. EPI-hNE4 can be nebulized efficiently without decrease in its activity. Mixing this inhibitor with (99m)Tc HSA should allow quantification of its deposition in CF patients.

Characterization of different vitamin E carriers intended for pulmonary drug delivery.

The targeted release of drugs intended for pulmonary delivery is a research field which has been so far rather unexploited but is currently becoming increasingly attractive. Liquid dispersions encapsulating vitamin E (liposomes, micelles, nano-emulsion, and solid lipid particles) were prepared using various methods based on membrane contactor. The dispersions were nebulized and aerodynamic characteristics of the generated aerosols were assessed using two different methods: laser light scattering and cascade impaction. When the laser diffraction technique was used, results showed that fine particle fractions (<5 µm) were 19, 29, 38 and 71% for solid lipid particles, micelles, nano-emulsion and liposomes, respectively. When the impaction method was applied, using a next generation pharmaceutical impactor operated at 30 l/min, results showed that fine particle fractions were 39, 78, 82 and 87% for solid lipid particles, micelles, nano-emulsion and liposomes, respectively. The differences observed between the results obtained from both methods confirm that the laser diffraction method is not always suitable for aerodynamic characterization of aerosols and should be validated against an impaction method. Nebulization of the drug-carrier systems led to an increase of their size most likely due to aggregation phenomena. The size was increased by a factor of 2-26 depending on the encapsulation system. The most important aggregation was obtained with nano-emulsion; the less one with solid lipid particles. The mass median aerodynamic diameter (MMAD) of the generated aerosols ranged from 1.76 to 6.10 µm. The application of a mathematical model, the Multiple-Path Particle Dosimetry (MPPD), for the prediction of the pulmonary deposit gave encouraging results. The rate of vitamin E able to reach the lung ranged from 37.6 (for the liposomes) to 51.6% (for the micelles). The obtained results showed that the different systems developed for vitamin E encapsulation were suitable to target the lung after pulmonary administration by nebulization.

[Inhaled treatments in cystic fibrosis: what's new in 2013?]. / Mucoviscidose et traitements inhalés: quoi de neuf en 2013?

In the past few years some new inhaled drugs and inhalation devices have been proposed for the treatment of cystic fibrosis. Breath-controlled nebulizers allow increased pulmonary deposition, with a lower variability and a shorter delivery time. The new dry powder formulations of tobramycin, colistine and mannitol require a change in the inhalation technique which must be slow and deep. In the field of the inhaled mucolytic drugs, hypertonic saline and mannitol have an indication in some patients. With regard to antibiotics, dry-powder tobramycin and colistine can be substituted for the same drug delivered by nebulization. Nebulized aztreonam needs more studies to determine its place. These new treatments represent a definite advance for cystic fibrosis patients and need to be known by all practitioners. Their position in our therapeutic arsenal remains to be accurately defined.

Aerosol delivery through tracheostomy tubes: an in vitro study.

BACKGROUND: Our study investigated the influence of the cannula's inner diameter (ID) and of its removal on the expected respiratory dose of amikacin, using three different jet nebulizer configurations (Sidestream(®)): vented (N1), unvented with a piece of corrugated tubing attached to the expiratory limb of the T attachment (N2), and unvented alone (N3). METHODS: The jet nebulizer was filled with amikacin (500 mg/4 mL) and was attached to the tracheostomy tube. A lung model simulating spontaneous breathing was connected to the tracheostomy tube. A filter was connected between the nebulizer and the tracheostomy tube to measure the inhaled dose, and between the tracheostomy tube and the lung model to measure the respiratory dose. Different cannula IDs were tested (6.5, 8, 8.5, and 10 mm), and aerosol lost in the cannulas was determined. RESULTS AND CONCLUSIONS: Respiratory dose varied between 96±1 mg and 44±3 mg, with higher values observed with N2. The aerosol lost in the cannula was significant and represented up to 63% of the inhaled dose. There was a negative correlation between the cannula's ID and the aerosol lost in the cannula. After removal of the internal cannula, an increase in the respiratory dose of up to 31.3% was observed. We recommend removing the inner tracheostomy cannula to nebulize a larger amount of drug through a tracheostomy tube. Among the three jet nebulizer configurations studied, we recommend the unvented one with a piece of corrugated tubing attached to the expiratory limb of the T attachment.

[Inhalation therapy: inhaled corticosteroids in ENT, development and technical challenges of powder inhalers, nebulisers synchronized with breathing and aerosol size distribution. GAT aerosolstorming, Paris 2012]. / Aérosolthérapie : les corticoïdes inhalés en ORL, le développement et les défis techniques des inhalateurs de poudre, les nébuliseurs couplés à la respiration et la granulométrie d'un aérosol. Aerosolstorming du GAT, Paris 2012.

The working group on aerosol therapy (GAT) of the Société de Pneumologie de Langue Française (SPLF) has organized its third Aerosolstorming in 2012. During one single day, different aspects of inhaled therapies have been treated and are detailed in two articles, this one being the second. This text deals with the indications of inhaled corticosteroids in ENT, the development and technical challenges of powder inhalers, the advantages and disadvantages of each type of technologies to measure the particle sizes of inhaled treatments.

Aerosol delivery to the lung is more efficient using an extension with a standard jet nebulizer than an open-vent jet nebulizer.

BACKGROUND: Open-vent jet nebulizers are frequently used to promote drug deposition in the lung, but their clinical efficacy and indications are not clear. Our study compared lung deposition of amikacin using two different configurations of a jet nebulizer (Sidestream(®)): one vented (N1) and one unvented with a corrugated piece of tubing (N2). METHODS: In vitro nebulizer performance was assessed by laser diffraction and filtering. Lung delivery was evaluated by scintigraphy in baboons as a child model, and by amikacin urinary drug concentration in seven healthy spontaneously breathing volunteers. Subjects were randomly assigned to the two nebulizer systems (N1 and N2). RESULTS AND CONCLUSIONS: In vitro results showed a higher efficiency of N2 than N1 in terms of lung deposition prediction (95±3 mg vs. 70±0 mg; p<0.0001). Radioactivity deposition in the baboons' lungs was lower with N1 than with N2 (1.8% vs. 4.7% of nebulizer charge; p<0.05). The total daily amount of amikacin urinary excretion was lower with N1 than with N2 (29.5 mg vs. 40.1 mg; p<0.01). Conversely, in vivo drug output rate was higher with N1 than with N2 (3.1 mg/min vs. 2.2 mg/min; p<0.05). Using a corrugated piece of tubing with standard jet nebulizers delivers higher doses to the lungs than open-vent jet nebulizers. The open-vent jet nebulizer might be recommended for rapid administration of a lower dose to the lungs and the standard jet nebulizer with corrugated piece of tubing for a higher dose in the lungs.

Pulmonary delivery of dry powders to rats: tolerability limits of an intra-tracheal administration model.

The inhaled route is increasingly developed to deliver locally acting or systemic therapies, and rodent models are used to assess tolerance before clinical studies. Endotracheal intubation of rats with a probe which generates powder aerosols enables controlled administration of drug directly into the respiratory tract. However, preliminary observations of intratracheal powder administration procedures have raised concerns with regard to pulmonary safety. The aim of the present work was to evaluate the safety of intra-tracheal administration of dry powder in a rat model. Sixty animals were administered various volumes of air alone, lactose or magnesium stearate through a Microsprayer(®) (Pencentury, USA). The mass of powder actually delivered to each animal was calculated. Rats were sacrificed immediately after administration, and the lungs, trachea and larynx were removed and examined for gross pathology. The mass of powder delivered varied, the full dose being rarely delivered. About one third of the administration procedures resulted in respiratory failure, and macroscopic pulmonary lesions were observed in about 55% of animals. Lung damages were observed with air alone, lactose and magnesium stearate. In conclusion, artifacts observed with this technique may limit the relevance of the model. These observations are particularly important in the context of regulatory toxicity studies.