title: Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates.
abstract: In pre-clinical animal studies, the uniformity of dosing across subjects and routes of administration is a crucial requirement. In preparation for a study in which aerosolized live-attenuated measles virus vaccine was administered to cynomolgus monkeys (Macaca fascicularis) by inhalation, we assessed the percentage of a nebulized dose inhaled under varying conditions.
  
  
  
  Drug delivery varies with breathing parameters. Therefore we determined macaque breathing patterns (tidal volume, breathing frequency, and inspiratory to expiratory (I:E) ratio) across a range of 3.3-6.5 kg body weight, using a pediatric pneumotachometer interfaced either with an endotracheal tube or a facemask. Subsequently, these breathing patterns were reproduced using a breathing simulator attached to a filter to collect the inhaled dose. Albuterol was nebulized using a vibrating mesh nebulizer and the percentage inhaled dose was determined by extraction of drug from the filter and subsequent quantification.
  
  
  
  Tidal volumes ranged from 24 to 46 mL, breathing frequencies from 19 to 31 breaths per minute and I:E ratios from 0.7 to 1.6. A small pediatric resuscitation mask was identified as the best fitting interface between animal and pneumotachometer. The average efficiency of inhaled dose delivery was 32.1% (standard deviation 7.5, range 24%-48%), with variation in tidal volumes as the most important determinant.
  
  
  
  Studies in non-human primates aimed at comparing aerosol delivery with other routes of administration should take both the inter-subject variation and relatively low efficiency of delivery to these low body weight mammals into account.
authors.affiliation: 1 Aerogen Ltd., Galway Business Park, Galway, Ireland.
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: MacLoughlin
authors.affiliation: 2 Department of Viroscience, Erasmus MC , Rotterdam, Netherlands .
authors.forename: Geert
authors.initials: G
authors.lastname: van Amerongen
authors.affiliation: 3 Division of Respiratory Therapy, Georgia State University , Atlanta, Georgia .
authors.forename: James B
authors.initials: JB
authors.lastname: Fink
authors.affiliation: 4 Department of Pediatric Pulmonology, Erasmus MC-Sophia Children's Hospital , Rotterdam, Netherlands .
authors.forename: Hettie M
authors.initials: HM
authors.lastname: Janssens
authors.affiliation: 5 Department of Microbiology, Boston University School of Medicine , Boston, Massachusetts.
authors.forename: W Paul
authors.initials: WP
authors.lastname: Duprex
authors.affiliation: 2 Department of Viroscience, Erasmus MC , Rotterdam, Netherlands .
authors.forename: Rik L
authors.initials: RL
authors.lastname: de Swart
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D000336:Aerosols; D000420:Albuterol / Q000008:administration & dosage*; D000818:Animals; D001835:Body Weight; D016503:Drug Delivery Systems / Q000295:instrumentation*; D054796:Drug Dosage Calculations; D004867:Equipment Design; D008168:Lung / Q000503:physiopathology*; D008252:Macaca fascicularis; D008297:Male; D008397:Masks; D023421:Models, Animal; D009330:Nebulizers and Vaporizers; D012119:Respiration; D015656:Respiratory Mechanics; D013990:Tidal Volume
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000336:Aerosols; D000420:Albuterol
keywords: cynomolgus macaques; inhaled dose; non-human primates; tidal breathing; vibrating mesh nebulizer