In VitroTests for Aerosol Deposition. IV: Simulating Variations in Human Breath Profiles for Realistic DPI Testing

Abstract

Background: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs. time profile (IP) is designated the total lung dose in vitro, or TLD in vitro . This article describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance (R) provided subjects followed written instructions either alone or in combination with formal training. Methods: In a drug-free clinical trial, inhaler-naïve, nonsmoking healthy adult human volunteers were screened for normal pulmonary function. IPs were collected from each volunteer inhaling through different air flow resistances after different levels of training. IPs were analyzed to determine the distribution of inhalation variables across the population and their dependence on training and airflow resistance. Results: Equations for IP simulation are presented that describe the data including confidence limits at each resistance and training condition. Realistic IPs at upper (90%), median (50%), and lower (10%) confidence limits were functions of R and training. Peak inspiratory flow rates (PIFR) were inversely proportional to R so that if R was assigned, values for PIFR could be calculated. The time of PIFR, T PIFR , and the total inhaled volume (V) were unrelated to R, but dependent on training. Once R was assigned for a powder inhaler to be tested, a range of simulated IPs could be generated for the different training scenarios. Values for flow rate acceleration and depth of inspiration could also be varied within the population limits of T PIFR and V. Conclusions: The use of simulated IPs, in concert with realistic in vitro testing, should improve the DPI design process and the confidence with which clinical testing may be initiated for a chosen device.

Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung

“…(58,(62)(63)(64)(65) Simulation of realistic patient inhalation maneuvers during in vitro testing, potentially including simulation of mis-use, (66) can also be important in establishing in vivo-in vitro correlations, in particular for DPIs where emitted doses and aerosol size distributions are flow-rate dependent. (20,67,68) Results of in vitro experiments have also been used to validate models or to derive analytical correlations that can be used in lieu of deposition models, especially for extrathoracic deposition. (62,63,65,69) Such correlations must be applied with caution in predicting ADD or total aerosol deposition from single-breath inhalers, as discussed above in the previous section.…”

Budesonide/Formoterol Easyhaler®: Performance Under Simulated Real-Life Conditions

“…In addition, different authors have published substantial work related to the use of more realistic patient air flow profiles, e.g. Koening et al [22] and Delvadia et al [23]. These advanced methods in combination with pharmacokinetic results would possibly establish more depth of understanding in vitro/in vivo (IVIV) correlation between different products and provide valuable tools for the development in the future.…”

Innovation for Generic Drugs: Science and Research Under the Generic Drug User Fee Amendments of 2012

“…The FDA has a series of research projects that explore various in vitro options, which can support generic drug development programs for orally inhaled drug products (OIDPs) by streamlining the current regulatory pathways or even replacing the less sensitive, time‐consuming, and costly comparative clinical end point bioequivalence study currently recommended under a weight‐of‐evidence approach. These projects include research to create and validate a sensitive and predictive dissolution test system, methods for comparative cascade impaction, and efforts to establish more predictive in vitro methods to investigate and compare the total dose and the aerodynamic particle size distribution of different OIDPs exiting different mouth‐throat models under realistic inhalation flow conditions . These new in vitro tests can also aid generic product developers in understanding the impact of both manufacturing processes and excipient sources on batch to batch variability.…”