Respiratory safety pharmacology - current practice and future directions

Area of Science:

• Pharmacology
• Respiratory Physiology
• Drug Safety Assessment

Background:

• Current respiratory safety pharmacology, guided by ICH S7A, primarily focuses on pulmonary ventilation measurements.
• Standard parameters include respiratory rate, tidal volume, and arterial blood gases, which assess ventilation but may lack mechanistic insight.
• These methods do not fully evaluate the gas exchange unit (lung) or airway function.

Purpose of the Study:

• To highlight the limitations of current ventilatory assessment in respiratory safety pharmacology.
• To advocate for the inclusion of additional parameters for a comprehensive evaluation of drug-induced respiratory dysfunction.
• To emphasize the importance of assessing gas exchange and airway function alongside ventilation.

Main Methods:

• Review of current practices in respiratory safety pharmacology based on ICH S7A guidelines.
• Identification of standard ventilatory measurement parameters (respiratory rate, tidal volume, blood gases).
• Discussion of additional parameters for mechanistic insight (inspiratory/expiratory times/flows, apneic time) and functional reserve (stimulation models).
• Exploration of methods to assess the gas exchange unit (airway patency, lung elastic recoil, gas diffusion capacity).

Main Results:

• Current practices adequately measure ventilation but may miss drug-induced effects on gas exchange and airway function.
• Additional parameters like inspiratory/expiratory times, apneic time, and stimulation models can enhance sensitivity and quantify functional reserve.
• Assessing airway patency, lung elastic recoil, and gas diffusion capacity is crucial for characterizing drug effects on the lung's gas exchange unit.

Conclusions:

• A comprehensive approach to respiratory safety pharmacology requires evaluating both ventilation and gas exchange.
• Incorporating diverse methodologies and measurement endpoints is essential for detecting and characterizing drug-induced respiratory dysfunction.
• Future studies should integrate assessments of airway patency, lung mechanics, and diffusion capacity for robust safety evaluations.