Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates

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.

Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo

“…After completion of ferret experiments, cynomolgus macaques were inoculated with 10 9 PFU rMVA-GFP by IM injection or aerosol (AER) inhalation 24 – 26 . Slices from either the hind leg muscle or lungs obtained from non-human primates at necropsy 6 HPA were analysed by direct CLSM, which revealed presence of GFP + cells after IM injection or AER inhalation, respectively (Fig.…”

Nasal high flow nebulization in infants and toddlers: An in vitro and in vivo scintigraphic study

“…Similarly, the in vivo model does not enable control of breathing pattern which may differ in the lightly sedated animals as compared to patients. However, recent data indicate that in terms of milliliter per kilogram of body weight of tidal volume, macaques represent a relevant human model . Those potential limitations related to breathing patterns mainly apply to the absolute values of aerosol lung deposition reported, which may be slightly different in patients.…”

“…However, recent data indicate that in terms of milliliter per kilogram of body weight of tidal volume, macaques represent a relevant human model. 25 Those potential limitations related to breathing patterns mainly apply to the absolute values of aerosol lung deposition reported, which may be slightly different in patients. However, as breathing patterns set on the in vitro model and animal experimental conditions were strictly equal in all experiments, differences observed between aerosol delivery conditions (i.e., comparison between vibrating mesh nebulization within the NHF circuit and control jet nebulization) may not have been affected by breathing pattern changes.…”

In Vitro Study of the Effect of Breathing Pattern on Aerosol Delivery During High-Flow Nasal Therapy

“…Bhasyham et al [12] showed that aerosol output dose increased from 18.6% with a tidal volume of 150 ml to 25.4% with a tidal volume of 300 ml during simulated HFNT. El Taoum et al [40] evaluated the delivery of aerosols via the nasal route with face masks in a 7-month and a 5-year-old head [41] showed that variation in tidal volume was the most important determinant for aerosol delivery to non-human primates. It is noteworthy that tidal volume was the parameter with the least effect during an adult breathing pattern, but had the greatest effect in small child and infant breathing.…”