title: In Vitro Tests 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 TLDin 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, TPIFR, 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 TPIFR 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.
authors.affiliation: 1 Food and Drug Administration , Rockville, Maryland.
authors.forename: Renishkumar R
authors.initials: RR
authors.lastname: Delvadia
authors.affiliation: 2 School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: Xiangyin
authors.initials: X
authors.lastname: Wei
authors.affiliation: 3 School of Engineering, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: P Worth
authors.initials: PW
authors.lastname: Longest
authors.affiliation: 2 School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Venitz
authors.affiliation: 2 School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Byron
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000403:Airway Resistance; D000465:Algorithms; D003198:Computer Simulation; D058995:Dry Powder Inhalers; D004867:Equipment Design; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008168:Lung / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D010174:Pamphlets; D010353:Patient Education as Topic / Q000379:methods; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D011208:Powders; D012119:Respiration; D013997:Time Factors; D055815:Young Adult
chemical_list: D000336:Aerosols; D004364:Pharmaceutical Preparations; D011208:Powders
keywords: airflow resistance; dry powder inhaler; in vitro–in vivo correlations; inhalation profiles; patient training; peak inhalation flow rate; realistic inhaler testing