Respiratory safety pharmacology - Current practice and future directions

- Respiratory safety pharmacology studies are currently guided by the strategy and endpoints defined in the ICH S7A regulatory document.
- Current practice is limited in that it does not provide optimum methodology for characterizing changes in ventilation.
- Current practice is limited in that it does not address methods needed to characterize effects on lung airways and lower respiratory tract.
- Current practice could be enhanced by providing a core strategy to better detect breathing abnormalities and lung dysfunction.
- Current practice could be enhanced by adding new follow up measurement endpoints to further characterize drug effects on the lower respiratory tract.
- Future directions should include characterizing drug effects in disease and stress animal models to better understand clinical significance.

Current practice in respiratory safety pharmacology generally follows the guidance provided by the ICH document S7A and, in general, focuses on measures of pulmonary ventilation. Respiratory rate, tidal volume and/or a measure of arterial blood gases are the recommended ventilatory measurement parameters. Although these parameters will provide a measure of ventilation, other ventilatory parameters, which can provide mechanistic insight, should also be considered. Such parameters include inspiratory and expiratory times and flows and apneic time. Stimulation models involving exercise and exposure to elevated CO2 or reduced O2 should also be considered when enhancing measurement sensitivity or quantifying reductions in ventilatory functional reserve are desired. Although ventilatory measurements are capable of assessing the functional status of the respiratory pumping apparatus, such measurements are generally not capable of assessing the status of the other functional component of the respiratory system, namely, the gas exchange unit or lung. To characterize drug-induced effects on the gas exchange unit, measures of airway patency, lung elastic recoil and gas diffusion capacity need to be considered. Thus, a variety of methodologies and measurement endpoints are available for detecting and characterizing drug-induced respiratory dysfunction in animal models and should be considered when designing respiratory safety pharmacology studies.