Safety pharmacology studies aim to predict the clinical safety of potential drug candidates based on a set of harmonized preclinical experiments designed to evaluate pharmacological effects on vital body functions (ICH S7A Guidelines). For the respiratory system, the current practice is to look at the effect of novel therapeutic agents in conscious animals, predominately rodents. In such studies, there is a preference for conscious respiratory function measurements as they fully encompass all aspects of the respiratory system’s function (i.e. the nervous, muscular and gas exchange components), thus providing physiologically-relevant and translational outcomes.
The non-invasive double chamber plethysmograph is a proven way to study pulmonary function in restrained, conscious animals. This technique has become the current industry standard as subjects are spontaneously breathing and are free of any effects of anaesthesia or other influences. Due to a seal around the restraint, a distinction can be made between the nasal and thoracic cavities, providing true respiratory flow measurements that comply with ICH S7A Guidelines.
- Respiratory Function Assays in Safety Pharmacology – D Murphy – Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays – 2013
- Lung Function Measurements in Rodents in Safety Pharmacology – Studies H G Hoymann – Frontiers in Pharmacology, 2012
- Respiratory safety pharmacology: Positive control drug responses in Sprague–Dawley rats, Beagle dogs and cynomolgus monkeys – S Authier et al. – Regulatory Toxicology and Pharmacology, 2009
- Measuring lung function in mice: the phenotyping uncertainty principle. – Bates et al. – J Appl. Physiology, 1985
TRANSLATIONAL MEASUREMENTS IN CONSCIOUS LARGE ANIMALS.
Non-rodent species are also commonly used in safety pharmacology studies. In these species (Beagle dogs, non-human primates), the pharmacological effects of novel therapeutic agents on the respiratory system can be studied in a refined manner using the tremoFlo. This portable, non-invasive system combines measurements of core respiratory endpoints (tidal volume, respiratory rate) to a respiratory mechanics assessment by airwave oscillometry. This approach provides additional insight into airway resistance and lung compliance for an exhaustive, respiratory safety pharmacology assessment of novel therapeutic agents. This technique is also employed in a clinical setting to assess patients thus providing translational outcomes.
- Non-invasive measure of respiratory mechanics and conventional respiratory parameters in conscious large animals by high frequency airwave oscillometry – Authier et al. J Pharmacol Toxicol Methods 70:52, 2014
- Nonclinical strategy considerations for safety pharmacology: evaluation of biopharmaceuticals – Vargas et al. Expert Opin Drug Saf 12:91, 2013
- Optimizing the use of methods and measurement endpoints in respiratory safety pharmacology – Murphy. J Pharmacol Toxicol Methods 70:204, 2014
EFFICIENT PRELIMINARY INHALATION STUDIES.
Health risks to inhaled novel therapeutic agents are typically evaluated in preclinical inhalation studies. These studies are frequently conducted using large scale exposure platforms with large numbers of subjects and important quantities of test material. The inExpose, a compact precision inhalation exposure system, offers investigators an alternative to run small scale studies to evaluate a reduced number of subjects, narrow experimental conditions or endpoints, or minimize compound requirements. Due to its small internal volumes, the inExpose reaches target concentrations quickly using reduced quantities of test material in a standard laboratory environment. Particulate monitoring devices can be incorporated for quantitative, qualitative, or semi-quantitative readings of the density of suspended particulates to compare one experiment to the next.
- SCIREQ Application Note 013 – Reproducible Respiratory Research
- Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers – Patlolla et al. J Contr Release 144: 233, 2010
- Pulmonary biocompatibility assessment of inhaled single-wall and multiwall carbon nanotubes in BALB/c mice – Ravichandran et al. J Biol Chem 286: 29725-29733, 2011
OUTCOMES BEYOND STANDARD ENDPOINTS.
While the regulatory guidelines require that respiratory safety pharmacology studies be conducted in conscious subjects, changes in the parameters typically monitored (respiratory rate, tidal volume, minute ventilation) may not necessarily reflect direct pharmacological effects on the respiratory system. Effects on other systems (central nervous or cardiovascular system) can indirectly affect the respiratory function and the ventilatory parameters monitored. The information needed for a clear assessment of direct pharmacological effects on the respiratory system can be obtained with the flexiVent, which utilizes a more invasive technique and controls the experimental environment during measurements. This offers highly reproducible, detailed outcomes that go beyond the standard safety respiratory endpoints, which can help eliminate false positives early on. The concurrent use of the flexiVent in safety pharmacology studies can provide valuable insights on respiratory mechanisms or novel therapeutic agents, which can fast-track the necessary regulatory process leading to clinical trials.