Studies in Aerosol Drug Formulation, Analysis, and Modeling

A recently mandated change in the use of pharmaceutical propellants spurred the development and reevaluation of aerosolized pharmaceuticals. Chlorofluorocarbon (CFC) propellants were commonly used in pressurized metered dose inhalers (MDIs), but were unfortunately linked to the depletion of the ozone layer. As such, a search for new propellants was initiated and ultimately resulted in the implementation of hydrofluoroalkane (HFA) propellants in MDIs. These HFA propellants however demonstrated significantly different properties than CFCs and necessitated a considerable amount of reformulation efforts. Not only did HFAs demonstrate different physiochemical properties, but in some cases these differences necessitated reengineering of the delivery device. Unfortunately HFA propellants are considered greenhouse gasses, albeit to a lesser degree than CFCs, so the development of alternate delivery methods has been ongoing. One delivery method that has received significant attention and resources is dry powder inhalers (DPIs). DPIs are a propellant-free alternative to aerosolized drug delivery, and demonstrate some advantages and disadvantages compared to the use of MDIs and nebulizers.In addition to the modernization of pharmaceutical agents, excipients, and delivery devices, technological advances have allowed for different and/or improved characterization of pharmaceutical aerosols. Particle size characteristics of aerosols are the primary physical measure examined and are relevant to ensure proper and reproducible drug delivery to the lung. Likewise, chemical analysis of the pharmaceutical agent is extremely important for pharmaceutical development and monitoring, including solubility determination, stability monitoring, and ultimately, dose emitted. Because many limitations exist in characterization however, and because experimental means can be costly with regard to labor and materials, prediction of aerosol performance characteristics based on formulation and device variables are valuable.Previous work predicting the performance of solution based MDIs has opened the door for improved prediction of suspension based MDI systems. Suspension aerosol prediction has been examined in the past, but additional information is now available to more appropriately model suspension MDI systems that include polydisperse drug material and emit polydisperse droplets

Population pharmacokinetics and exposure‐response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID‐19

Abstract Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non‐hospitalized high‐risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure‐response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between‐participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two‐compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first‐order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET‐TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model‐estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure‐progression relationship across severe acute respiratory syndrome‐coronavirus 2 variants

Inhalation of an Ethanol-Based Zileuton Formulation Provides a Reduction of Pulmonary Adenomas in the A/J Mouse Model

Potential efficacy of zileuton, a 5-LOX inhibitor, was evaluated for the reduction of pulmonary adenomas in the A/J murine model when administered via nose-only inhalation. Development of pulmonary adenomas was induced with benzo(a)pyrene. Animals were treated with a zileuton solution (5 mg/mL in 85:15 ethanol/water) either twice weekly or five times a week via nose-only inhalation; The placebo solution (85:15 EtOH/H2O, no active) was also evaluated. Dose delivered was calculated to be 1.2 mg/kg per exposure for each zileuton group. After 20 weeks of treatment, surface tumors were enumerated and histologically assessed. A significant reduction in tumor count was noted for both the twice weekly administration (40%) and the five times a week administration (59%). The data also showed a significant reduction for the group, which received the placebo (approximately 58%). The treatment groups were also found to have an impact on the histological stages of adenoma development