Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates
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.
|Keywords||cynomolgus macaques, inhaled dose, non-human primates, tidal breathing, vibrating mesh nebulizer|
|Persistent URL||dx.doi.org/10.1089/jamp.2015.1250, hdl.handle.net/1765/93835|
|Journal||Journal of Aerosol Medicine and Pulmonary Drug Delivery|
MacLoughlin, R.J. (Ronan J.), van Amerongen, G, Fink, J.B. (James B.), Janssens, H.M, Duprex, W.P, & de Swart, R.L. (2016). Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 29(3), 281–287. doi:10.1089/jamp.2015.1250