Optimizing the use of methods and measurement endpoints in respiratory safety pharmacology.
A variety of methods and measurement endpoints are currently available for evaluating respiratory function in animal models. To evaluate drug-induced effects on respiratory function, respiratory safety pharmacology studies generally emphasize the use of conscious animal models and measures of pulmonary ventilation. Respiratory rate, tidal volume and/or a measure of arterial blood gases are the standard measurement parameters. Although these parameters will provide a measure of ventilation, other ventilatory parameters, which can provide mechanistic insight or identify site of action, should also be considered. Such parameters include inspiratory and expiratory times, flows and pauses, 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 is 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. The objective of this review is to discuss the value and utility of the methods and measurement endpoints currently available for assessing respiratory function to help optimize the design of respiratory safety pharmacology studies.
Department of Safety Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA. Electronic address: dennis.j.murphy@gsk.com.
Dennis J
DJ
Murphy
D000818:Animals; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D006801:Humans; D012137:Respiratory System / Q000187:drug effects*; D012449:Safety
Function; Methods; Nonclinical; Pulmonary; Respiratory; Safety Pharmacology