Inhaled remdesivir reduces viral burden in a nonhuman primate model of SARS-CoV-2 infection.

Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients with coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as the first treatment for hospitalized COVID-19 patients. Furthermore, RDV has been approved or authorized for emergency use in more than 50 countries. To make RDV more convenient for non-hospitalized patients earlier in disease, alternative routes of administration are being evaluated. Here, we investigated the pharmacokinetics and efficacy of RDV administered by head dome inhalation in African green monkeys (AGM). Relative to an IV administration of RDV at 10 mg/kg, an approximately 20-fold lower dose administered by inhalation produced comparable concentrations of the pharmacologically active triphosphate in lower respiratory tract tissues. Distribution of the active triphosphate into the upper respiratory tract was also observed following inhaled RDV exposure. Inhalation RDV dosing resulted in lower systemic exposures to RDV and its metabolites as compared with IV RDV dosing. An efficacy study with repeated dosing of inhaled RDV in an AGM model of SARS-CoV-2 infection demonstrated reductions in viral replication in bronchoalveolar lavage fluid and respiratory tract tissues compared with placebo. Efficacy was observed with inhaled RDV administered once daily at a pulmonary deposited dose of 0.35 mg/kg beginning approximately 8 hours post-infection. Moreover, the efficacy of inhaled RDV was similar to that of IV RDV administered once at 10 mg/kg followed by 5 mg/kg daily in the same study. Together, these findings support further clinical development of inhalation RDV.

Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract?

This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat. Low-density porous particles are able to largely bypass URT deposition due to the fact that both the primary particles and their agglomerates are respirable. The low-density particles also exhibit dose delivery to the lungs that is largely independent of inspiratory flow rate across a range of flow rates that most subjects achieve with portable DPIs. Coupling this with delivery devices that are breath actuated, simple to operate (open-inhale-close), and have adherence-tracking capability enables drug delivery that is largely independent of how a subject inhales, with a user experience that is close to that of an "idealhaler."

Improvement of an In Vitro Model to Assess Delivered Dose and Particle Size for a Vibrating Mesh Nebulizer During Mechanical Ventilation.

BACKGROUND: In an in vitro model of mechanical ventilation with gravity-dependent filter position we observed artificially high delivered doses resulting from liquid droplet collection and precipitation of aerosolized drug. We sequentially modified the model to obtain accurate reproducible measurements of delivered dose and particle size at endotracheal tube exit. METHODS: Stepwise changes in the model included (1) altering the endotracheal tube position to a gravity-independent position, (2) adding fluid traps, (3) humidifying air near the test lung, and (4) simplifying test lung and filters. Delivered dose of aerosolized vancomycin and losses in different compartments were assessed under low-flow and high-flow conditions, with or without circuit humidification. Droplet size distribution (DSD) of aerosolized Amikacin Inhalation Solution at endotracheal tube exit was measured by laser diffraction. RESULTS: Changing endotracheal tube position and adding traps allowed separation of liquid droplets and aerosolized drug, providing a delivered vancomycin dose of 35.1% (high flow). Active heated humidification of exhaled air significantly reduced delivered dose (21.0%) and dose variability. Simplification of the model to improve usability had no further effect on delivered dose, which was higher under low-flow than high-flow conditions, although there was no difference between humidified (high flow, 20.3%; low flow, 45.8%) and nonhumidified (high flow, 22.8%; low flow, 47.3%) conditions. With circuit humidification, drug loss decreased in endotracheal tube and nebulizer T-piece, whereas more drug was captured in traps. Lower inspiratory flow and humidity in the circuit were associated with higher Dv50 of aerosolized Amikacin Inhalation Solution at endotracheal tube exit. CONCLUSIONS: We successfully modified our in vitro model of mechanical ventilation to allow more accurate measurement of the delivered dose of aerosolized vancomycin and DSD profile of aerosolized Amikacin Inhalation Solution at the endotracheal tube exit.

A simplified guide for charged aerosol detection of non-chromophoric compounds-Analytical method development and validation for the HPLC assay of aerosol particle size distribution for amikacin.

Amikacin, an aminoglycoside antibiotic lacking a UV chromophore, was developed into a drug product for delivery by inhalation. A robust method for amikacin assay analysis and aerosol particle size distribution (aPSD) determination, with comparable performance to the conventional UV detector was developed using a charged aerosol detector (CAD). The CAD approach involved more parameters for optimization than UV detection due to its sensitivity to trace impurities, non-linear response and narrow dynamic range of signal versus concentration. Through careful selection of the power transformation function value and evaporation temperature, a wider linear dynamic range, improved signal-to-noise ratio and high repeatability were obtained. The influences of mobile phase grade and glassware binding of amikacin during sample preparation were addressed. A weighed (1/X2) least square regression was used for the calibration curve. The limit of quantitation (LOQ) and limit of detection (LOD) for this method were determined to be 5µg/mL and 2µg/mL, respectively. The method was validated over a concentration range of 0.05-2mg/mL. The correlation coefficient for the peak area versus concentration was 1.00 and the y-intercept was 0.2%. The recovery accuracies of triplicate preparations at 0.05, 1.0, and 2.0mg/mL were in the range of 100-101%. The relative standard deviation (Srel) of six replicates at 1.0mg/mL was 1%, and Srel of five injections at the limit of quantitation was 4%. A robust HPLC-CAD method was developed and validated for the determination of the aPSD for amikacin. The CAD method development produced a simplified procedure with minimal variability in results during: routine operation, transfer from one instrument to another, and between different analysts.

Application of a droplet evaporation model to aerodynamic size measurement of drug aerosols generated by a vibrating mesh nebulizer.

BACKGROUND: Droplet evaporation has been known to bias cascade impactor measurement of aerosols generated by jet nebulizers. Previous work suggests that vibrating mesh nebulizers behave differently from jet nebulizers. Unlike jet nebulizers, vibrating mesh nebulizers do not rely on compressed air to generate droplets. However, entrained air is still required to transport the generated droplets through the cascade impactor during measurement. The mixing of the droplet and entrained air streams, and heat and mass transfer occurring downstream determines the final aerosol size distribution actually measured by the cascade impactor. This study is aimed at quantifying the effect of these factors on droplet size measurements for the case of vibrating mesh nebulizers. METHODS: A simple droplet evaporation model has been applied to investigate aerodynamic size measurement of drug aerosol droplets produced by a proprietary vibrating mesh nebulizer. The droplet size measurement system used in this study is the Next Generation Impactor (NGI) cascade impactor. Comparison of modeling results with experiment indicates that droplet evaporation remains a significant effect when sizing aerosol generated by a vibrating mesh nebulizer. RESULTS AND CONCLUSIONS: Results from the droplet evaporation model shows that the mass median aerodynamic diameter (MMAD) measured by the NGI is strongly influenced not only by the initial droplet size, but also by factors such as the temperature and humidity of entrained air, the nebulizer output rate, and the entrained air flow rate. The modeling and experimental results indicate that the influence of these variables on size measurements may be reduced significantly by refrigerating the impactor down to 5°C prior to measurement. The same data also support the conclusion that for the case of nebulized drug solutions, laser diffraction spectrometry provides a meaningful droplet sizing approach, that is simpler and less susceptible to such droplet evaporation artifacts.