Exploratory Toxicology
Toxicity is one of the leading causes for candidate rejection during drug development. As a result, many scientists recognize the importance of including exploratory toxicology studies during the preclinical drug discovery phase, to minimize the risk of failure at the clinical level due to toxicological liabilities. When looking specifically at the field of respiratory drug discovery and development, these exploratory toxicology studies must provide physiologically-relevant, reproducible and translational data.
RELATED PRODUCTS
COMPREHENSIVE AND INTEGRATED ASSESSMENT.
During exploratory toxicology studies, the safety of a potential respiratory drug candidate can be evaluated by studying its impact on lung function. In-depth measurements using the flexiVent are acquired in a controlled experimental environment which provides highly reproducible, detailed outcomes that can prevent drug candidates with a safety risk from entering clinical development and also assist in understanding the toxicological properties of the drug candidate early on in the process to avoid costly late-stage failures.
REFERENCES
- Yang, Y.L et al. (2017). Hesperetin-5,7,3’-O-triacetate suppresses airway hyperresponsiveness in ovalbumin-sensitized and challenged mice without reversing xylazine/ketamine-induced anesthesia in normal mice. BMC Pharmacol Toxicolgy, 18(1):39
- Kim J.S (2011). Evaluating pulmonary toxicity of engineered metal-based nanoparticles using in vivo and in vitro models. Dissertation
- Katwa, P et al. (2012). A carbon nanotube toxicity paradigm driven by mast cells and the IL-₃₃/ST₂ axis. Small, 8(18):2904-12
- Phillips B et al. (2016) An 8-Month Systems Toxicology Inhalation/Cessation Study in Apoe-/- Mice to Investigate Cardiovascular and Respiratory Exposure Effects of a Candidate Modified Risk Tobacco Product, THS 2.2, Compared With Conventional Cigarettes. Toxicological Sciences, 149(2):411-32
- Phillips B et al. (2015) A 7-month cigarette smoke inhalation study in C57BL/6 mice demonstrates reduced lung inflammation and emphysema following smoking cessation or aerosol exposure from a prototypic modified risk tobacco product. Food and Chemical Toxicology, 80:328-345
COMPACT, REPRODUCIBLE, AUTOMATED.
Performing toxicology studies in relevant, practical animal models is key for translating the outcomes from the preclinical environment into understanding its toxicity risk in clinical trials. The inExpose is a compact and customizable inhalation exposure system, which provides a reproducible way of exposing animals to a drug candidate, creating relevant and reproductible animal models. The system offers sophisticated computer control for automated, precise, and repeatable aerosolised drug delivery using aerosol generation devices. Another highlight of the inExpose is that it offers small internal volumes which prevents unintended dilution of the drug candidate and removes the need for large quantities, further reducing costs.
REFERENCES
- Patel et al. Efficacy of Aerosolized Celecoxib Encapsulated Nanostructured Lipid Carrier in Non-small Cell Lung Cancer in Combination with Docetaxel. Pharmaceutical Research. 2013; 30(5):1435-1446.
- Ravichandran et al. Pulmonary biocompatibility assessment of inhaled single-wall and multiwall carbon nanotubes in BALB/c mice. Journal of Biological Chemistry. 2011; 286 (34): 29725-33.
- De Santis et al. – Efficacy of aerosol therapy of lung cancer correlates with EGFR paralysis induced by AvidinOX-anchored biotinylated Cetuximab. – Oncotarget. 2014 Aug;5(19):9239-55.
- Parlolla et al. Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers. J Control Release. 2010 Jun 1;144(2):233-41.
SYMPTOM SCREENING.
Non-invasive plethysmography techniques such as whole body plethysmography (WBP), double chamber plethysmography (DCP), or head-out plethysmography (HOP) can be used in exploratory toxicology studies to asses the toxicity risk of a candidate drug in conscious animals. This technique provides essential physiological information related to changes in respiratory function measurements such as tidal volume (Vt), respiratory rate (RR) and minute ventilation (MV).
Airway obstruction is one of the leading respiratory difficulties encountered during clinical trials of a drug candidate and although these techniques provide the advantage of assessment of respiratory function measurements, independent of anaesthetic side effects, the drawback is that these techniques do not provide information related to lung mechanics such as airway resistance.