Ronan J MacLoughlin1, Geert van Amerongen2, James B Fink3, Hettie M Janssens4, W Paul Duprex5, Rik L de Swart2. 1. 1 Aerogen Ltd., Galway Business Park, Galway, Ireland. 2. 2 Department of Viroscience, Erasmus MC , Rotterdam, Netherlands . 3. 3 Division of Respiratory Therapy, Georgia State University , Atlanta, Georgia . 4. 4 Department of Pediatric Pulmonology, Erasmus MC-Sophia Children's Hospital , Rotterdam, Netherlands . 5. 5 Department of Microbiology, Boston University School of Medicine , Boston, Massachusetts.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Arwen F Altenburg; Carolien E van de Sandt; Bobby W S Li; Ronan J MacLoughlin; Ron A M Fouchier; Geert van Amerongen; Asisa Volz; Rudi W Hendriks; Rik L de Swart; Gerd Sutter; Guus F Rimmelzwaan; Rory D de Vries Journal: Sci Rep Date: 2017-08-17 Impact factor: 4.379
Authors: Rik L de Swart; Rory D de Vries; Linda J Rennick; Geert van Amerongen; Stephen McQuaid; R Joyce Verburgh; Selma Yüksel; Alwin de Jong; Ken Lemon; D Tien Nguyen; Martin Ludlow; Albert D M E Osterhaus; W Paul Duprex Journal: NPJ Vaccines Date: 2017-08-01 Impact factor: 7.344