Respiratory Function as a Safety Concern in Drug Development

The respiratory system consists in three units: It functions under the influence of the central nervous system (CNS), exchanges gases in the lungs, and requires the cardiovascular system to carry the O2 to the organs and expel the CO2 via the lungs; consequently, it is sensitive to drug-induced effects on either the CNS, the lung itself, or the heart. Monitoring changes in respiration can therefore predict drug effects on either system in humans, provided an adequate species is selected, and the proper utilization of a multitude of modalities and instruments. This chapter discusses the use of noninvasive whole-body plethysmography as an add-on in discovery efficacy studies to highlight adverse respiratory effects, and the subsequent tests which can follow to ascribe the effect to either the CNS, the lungs, or the CV system. Respiratory mechanics, hemoglobin saturation monitoring, pressure-volume loops in the lungs, and apneic monitoring are presented with technical insight useful for laboratory investigators. Furthermore, late preclinical development safety pharmacology and investigative toxicology approaches are also discussed, involving induction and head-out plethysmography, as well as telemetry implantation methods in the rodents and larger animals typically used in respiratory safety assessment. Ultimately, the reader will be introduced to respiratory monitoring tools and approaches most useful in early and later preclinical drug development, and the technical knowledge which enhances the predictivity of these testing modalities.