Regulatory Toxicology and Pharmacology 69 (2014) 135–140

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Respiratory safety pharmacology – Current practice and future directions Dennis J. Murphy ⇑ Department of Safety Pharmacology, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA

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Article history: Received 24 October 2013 Available online 23 November 2013 Keywords: Regulatory Methods ICHS7A Safety pharmacology Respiratory Nonclinical PharmaPendium™

a b s t r a c t 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. Ó 2013 Elsevier Inc. All rights reserved.

1. Introduction Safety pharmacology is a discipline within the nonclinical (preclinical) assessment of drug safety. The current practice of respiratory function assessment within safety pharmacology generally follows the regulatory guidance as stated in the ICH S7A document, which was issued in 2001. (Anon, 2001) The guidance document defines safety pharmacology studies as those that ‘‘investigate the potential undesirable pharmacodynamic effects of a test substance on physiological functions in relation to exposure in the therapeutic range and above’’, with test substances including new chemical entities and biotechnology-derived products for human use. The core physiological functions for evaluation include those related to the cardiovascular, respiratory and central nervous systems. These systems were selected since they represent vital functions where acute dysfunction can lead to serious adverse events. Based on the guidance provided in the ICHS7A document, current respiratory safety pharmacology studies generally focus on the measures of pulmonary ventilation. Respiratory rate, tidal

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volume and/or a measure of arterial blood gases are the recommended ventilatory parameters. Although these parameters will provide a measure of ventilation, other parameters, which can provide mechanistic insight, should also be considered. Furthermore, it is important to note that the respiratory system consists of two functional components – the pumping apparatus and the gas exchange unit or lung (see Fig. 1). 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 gas exchange unit. To characterize drug-induced effects on the gas exchange unit, measures of airway patency, lung elastic recoil and/or gas diffusion capacity need to be considered. Methods for evaluating airway resistance and lung compliance are currently available for assessing airway patency and lung elastic recoil, respectively, in animal models (Diamond and O’Donnell, 1977; Costa, 1985). A variety of methodologies and measurement endpoints are currently available for assessing the effects of drugs on respiratory function in animal models. Because the current practice in respiratory safety pharmacology tends to focus on a limited number of respiratory parameters, the objective of this review is to discuss the value and utility of the many methodologies and measurement endpoints available to help optimize the design of respiratory safety pharmacology studies.


D.J. Murphy / Regulatory Toxicology and Pharmacology 69 (2014) 135–140

Respiratory System

Pumping Apparatus

Gas Exchange Unit

Funcon Regulate gas Exchange between environment and airways

Funcon Regulate gas exchange between airways and blood

Components Respiratory muscles, CNS, chemo/mechano-receptors

Components Airways, alveoli, vasculature, fibrous network

Measurements Tidal volume, respiratory rate, minute volume, inspiratory, expiratory & apneic mes

Measurements Airway resistance, lung compliance, gas diffusion capacity, PaO2/PaCO 2

Fig. 1. A chart of the functional and structural components of the respiratory system.

2. Methodology The methodology used to quantify the incidence of drug-induced effects on respiratory function in human clinical studies in this report involved use of the searchable database called PharmaPendium™ (Elsevier). This database contains the US Food and Drug Administration (FDA) Approval Package Database, the European Medicines Agency’s (EMEA) and European Public Assessment Reports (EPARs), the Adverse Event Reporting System (AERS) reports, Meyler’s Side effects of Drugs compendium and a pool of over 3000 journals and other worldwide sources. The search strategy used the sequential terms ‘‘adverse effects/toxicity (all sources)’’, ‘‘respiratory, thoracic and mediastinal disorders’’, and either ‘‘bronchial disorders (excluding neoplasms) – bronchospasm and obstruction’’ for identifying effects on airway resistance, the terms ‘‘respiratory disorders – breathing abnormalities’’ for identifying effects on ventilation and the terms ‘‘lower respiratory tract disorders (excluding obstruction and infection) – lower respiratory tract inflammation and immunologic conditions, parenchymal lung disorders (NEC) and pulmonary edema’’ for identifying effects on lower respiratory tract disorders. The results were then filtered for ‘‘clinical’’ findings and the time period of 2002–2012, to highlight the most recent findings of drug induced effects on the respiratory system. All results were transferred to Excel spreadsheets and manually checked for accuracy. 3. Evaluation of the current practice of using ventilatory endpoints alone to detect and characterize respiratory dysfunction A question that needs to be addressed is whether or not ventilatory parameters alone can provide the endpoints necessary to

evaluate drug-induced effects on the respiratory system. To address this question, the functional components of the respiratory system need to be considered (see Fig. 1). The respiratory system consists basically of two functional components – the pumping apparatus and the gas exchange unit. The function of the pumping apparatus is to regulate gas exchange between the environment and the airways to help ensure that sufficient oxygen is supplied to the circulation to meet changing metabolic demands and to remove excess carbon dioxide and other metabolic products. The components of the pump include the respiratory muscles, and the nerves, chemoreceptors and mechanoreceptors that regulate the depth and frequency of the pump. The other functional component is the gas exchange unit or lung. The function of the lung is to ensure that the gas which enters the airways is appropriately exchanged with pulmonary arterial blood. To do this, the lung must have patent airways to ensure movement of gases to the alveoli during inspiration and elastic recoil to ensure the removal of gases during expiration. The components of the gas exchange unit include the airways, alveoli, vasculature and elastic fibrous network. Change in the functional status of the pumping apparatus is determined by measuring ventilatory patterns, which should include the endpoints respiratory rate (frequency) and tidal volume (depth). By monitoring the frequency and depth of the pumping apparatus, the effects of drugs on total pulmonary ventilation (i.e., respiratory stimulation or depression) can be established. Monitoring ventilatory parameters, however, cannot generally be used to directly assess the status of the gas exchange unit or lung. Studies that have measured drug-induced effects on both ventilatory parameters and airway resistance have demonstrated that mild to moderate (2–3-fold) changes in airway resistance do not produce changes in breathing patterns in either animal models or humans. Studies in our laboratory have demonstrated that 2– 3-fold increases in airway resistance using an intravenous infusion of the bronchoconstrictive agent, methacholine, does not cause ventilatory changes in the rat, dog or monkey (unpublished results). Similar findings have been noted in humans (Savoy et al., 1984; Yasukouchi, 1992) and guinea pigs (Wiester et al., 2005). Thus, it appears that the absence of a change in ventilatory parameters cannot reliably predict the absence of mild to moderate changes in lung function. Measures of lung mechanics, which include airway resistance and lung compliance, are needed to assess airway patency and elastic recoil, respectively. Thus, to provide an assessment of drug-induced effects on both of the functional components of the respiratory system, ventilatory parameters and measures of airway resistance and lung compliance should be considered. Changes in airway resistance and lung compliance are important safety endpoints. An increase in airway resistance can result from obstruction of the airways caused the constriction of airway smooth muscle (bronchoconstriction), hypertrophy or hyperplasia of cells lining the airways, or hypersecretion of airway mucus. An increase in airway resistance can be an acute, life-threatening event with consequences equal to that produced by ventilatory defects such as hypoventilation and respiratory failure (Hunt and Rosenow, 1992). A decrease in lung compliance can result from alterations in lower respiratory tract, which may involve changes in fibrous network, presence of interstitial or intraalveolar fluid (edema) or inflammatory cells (pneumonitis), pulmonary congestion or surfactant disruption. Although not common, acute treatment with drugs can cause pulmonary edema or pneumonitis (Erasmus et al., 2002). More importantly, in repeat dose studies where alterations in the fibrous network, surfactant disruption or pulmonary congestion are more common (Erasmus et al., 2002), measuring compliance changes could be helpful by acting as an early biomarker for detecting lower respiratory tract disorders as well as providing an understanding of functional consequences.

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The importance of evaluating drug effects on lung function is supported by the finding that the number of drug products associated with airway obstruction or lower respiratory tract disorders is similar to that which causes ventilatory alterations in human clinical studies. Using the PharmaPendium™ database, a search on druginduced respiratory disorders showed that the percent of total drug products associated with breathing abnormalities (ventilatory alterations), airway obstruction or lower respiratory tract disorders were 40%, 29% and 31%, respectively. (Fig. 2) Thus, based on the respiratory system model involving two functional components, the poor reliability of ventilatory change to predict changes in airway resistance, and the known effects of drugs on both ventilatory and lung functions, including endpoints that assess both the pumping apparatus and the gas exchange unit should be considered for maximizing the ability to detect and characterize drug-induced respiratory dysfunction.

4. Evaluation of the current practice of using blood gas changes as a primary endpoint for detecting ventilatory changes Changes in the partial pressures arterial blood gases (PaO2 and PaCO2) and the use of hemoglobin oxygen saturation (SaO2) as a surrogate measure for PaO2 are currently accepted methods for assessing drug-induced ventilatory changes in safety pharmacology studies. To evaluate the value of these endpoints for assessing drug-induced changes in ventilation, two questions need to be addressed: (1) are changes in blood gases the most sensitive measure for detecting ventilatory effects? and (2) is SaO2 an appropriate


surrogate measure for arterial blood gases in respiratory safety pharmacology studies? To address the first question, changes in blood gases would not be expected to be a sensitive method for detecting a ventilatory defect in safety pharmacology studies. In safety pharmacology studies, healthy, conscious animals are used as the test subjects and, in healthy subjects, homeostatic mechanisms to prevent or minimize blood gas changes during a decrease or increase in lung ventilation are present. To compensate for a decrease in lung ventilation, the lung can minimize the change in blood gases by increasing the gas diffusing capacity of the lung. In general, the lung can increase gas diffusing capacity by approximately three fold (Hsia, 2002). This occurs by increasing lung perfusion, thereby decreasing physiological dead space that normally exists in the lung, and by increasing the number of alveoli that are ventilated. In addition, the blood has a buffering mechanism to minimize changes in plasma PaO2 and PaCO2 (Ellison et al., 1958; Brown and Clancy, 1965; Kovtun et al., 2011). This buffering system includes hemoglobin that binds O2 and minimizes changes in PaO2 and a carbonic anhydrase/bicarbonate system and proteins containing carbamino groups for buffering changes in PaCO2 during periods of reduced ventilation. Studies in healthy, conscious humans and animal models have confirmed this functional reserve. A study in humans demonstrated that a 100% increase in minute ventilation produced by removing a resistive load had no effect on end-tidal CO2 (Gallagher et al., 1985), while a study in dogs demonstrated that a 96% increase in minute ventilation produced by a respiratory stimulant (albuterol) had no effect on PaO2, PaCO2 or SaO2 (Authier et al., 2008). In conscious rats, reduced levels of

Fig. 2. A Comparison of Respiratory Abnormalities Identified in Clinical Trials over the period of 2002–2012. The bar graph is the absolute number of drug products associated with airway obstruction, breathing abnormalities, or lower respiratory tract abnormalities in human clinical trials, while the pie graph is the same data presented as percent of total. All data were obtained from the database PharmaPendium™.


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activity were associated with a up to a 40% reduction in minute ventilation with no change in PaO2 or PaCO2 (Polianski et al., 1984), while a reduction in minute ventilation by 30% using a respiratory depressant (morphine) produced no change in end tidal CO2 (Murphy et al., 1994). SaO2 is typically measured in humans and animals using a methodology call pulse oximetry. This is a non-invasive technology that involves attaching a photoelectric sensor to the surface of the body at a variety of locations including the ear, toe, finger, tail, paw, neck or tongue. The sensitivity of this methodology is limited in that the measurement occurs in a peripheral vascular bed and, being a surface measurement, can be influenced by a variety of factors including body temperature, localized vasoconstriction, room lighting and orientation of probe (Chan et al., 2013). The sensitivity of this method is also limited by the O2 buffering capacity of hemoglobin. The hemoglobin oxygen dissociation curve is sigmoidal in shape and, in a healthy subject, a decrease in PaO2 of approximately 20% is required before a significant change in hemoglobin oxygen saturation can occur. The lack of sensitivity of SaO2 for detecting blood gas changes was demonstrated in a study using healthy conscious dogs. In that study, minute ventilation was reduced by approximately 68% following the intravenous injection of a respiratory depressant (Remifentanil). The severe hypoventilation was associated with a 21% increase in PaCO2, a 14% decrease in PaO2 and no change in SaO2 (Authier et al., 2008). These findings indicate that a change in blood gases (especially SaO2) is not a sensitive measure of drug-induced ventilatory change in conscious, healthy animals as are used in safety pharmacology studies. Measures of tidal volume, respiratory rate and the derived minute volume are the most sensitive indicators of ventilatory change and, as such, are recommended for measuring druginduced effects on ventilatory function. Further, inclusion of both tidal volume and respiratory rate is important since the mechanisms controlling rate and volume are pharmacologically distinct with drugs that are known to affect ventilation generally doing so by selectively affecting either tidal volume or respiratory rate. For example, opioids such as morphine are known to cause respiratory depression in rats by affecting respiratory rate, with no effect on tidal volume, (Murphy et al., 1994) while the respiratory stimulant theophylline increases ventilation in rats by specifically affecting tidal volume with no effect on respiratory rate (Murphy et al., 1993).

5. Future directions 5.1. Modification of current practice A future direction for respiratory safety pharmacology should be one that includes practices that enhance our current ability to detect and characterize drug-induced effects on respiratory function. Current practice considers respiratory rate a standard parameter, but does not include tidal volume a standard measurement endpoint. Tidal volume is required for characterizing the effect of drugs that selectively alter ventilation through changes in the depth of breathing, (Murphy et al., 1993) and it is a required endpoint for calculating total pulmonary ventilation or minute volume. Minute volume is commonly used to identify and quantify respiratory stimulation or depression. Since a change in minute ventilation is more sensitive than arterial blood gas changes for detecting drug-induced effects on ventilation, tidal volume should be considered a fundamental endpoint. Arterial blood gas measurements, however, are important parameters for assessing the physiological consequences of severe ventilatory change and should be considered if needed to diagnose the occurence of hyperventilation or hypoventilation. Finally, hemoglobin oxygen saturation should

not be considered a standard endpoint for assessing changes in arterial blood gases because of the limitations previously mentioned and insensitivity of this measurement in conscious, healthy animal models (Authier et al., 2008). Another proposed modification to the current practice is to include airway resistance as a fundamental parameter in safety pharmacology studies. As previously mentioned, mild to moderate changes in airway resistance cannot generally be detected by changes in ventilatory patterns and 29% of the drug products associated with respiratory function disorders in clinical trials involve airway obstruction (Fig. 2). An increase in airway resistance is also an important safety endpoint since an acute drug-induced effect on lung airflow (e.g., bronchoconstriction) can be a life threatening event (Hunt and Rosenow, 1992). This rationale is consistent with the primary objective of safety pharmacology studies, which is to assess those ‘‘vital organs or systems, the functions of which are acutely critical for life’’. Airway resistance is quantified by measuring the transpulmonary pressure (mouth pressure–pleural pressure) required to achieve a given lung airflow. Methodologies are currently available for measuring airway resistance in rodents and non-rodents either during spontaneous breathing (dynamic resistance) or using a forced maneuver procedure that involves a controlled inflation and rapid deflation of the lung to evaluate forced expiratory flows (Diamond and O’Donnell, 1977; Costa, 1985). A measure of lung compliance should also be considered when there is a need to detect functional changes associated with druginduced injury to the lower respiratory tract. Such injury includes damage to alveoli and the interstitial components of the lung. Since these effects generally cause a decrease in lung elasticity, (MatuteBello et al., 2011) they can be detected by measuring lung compliance. The use of lung compliance measurement in single dose safety pharmacology studies may be limited in that lung injury rarely occurs following acute drug treatment or, if injury occurs, it can generally be detected by histopathological evaluation. However, inclusion of lung compliance as an endpoint should be considered when there is concern for acute lung injury following an inhaled dose of drug or when effects, which may not be detected by histopathological evaluation, such as interstitial edema or alterations in alveolar surfactant production, are anticipated. In repeat dose studies, lung compliance could be used as an in vivo biomarker for the onset and progression of drug-induced lung injury. Effects on the lower respiratory tract are characterized histopathologically as diffuse alveolar damage (with edema or hemorrhage), nonspecific interstitial pneumonia (with or without fibrosis) and bronchiolitis obliterans (Erasmus et al., 2002; Flieder and Travis, 2004). These types of changes are associated with the pathological syndromes of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) (Myers et al., 2003). Furthermore, approximately 31% of drug products associated with respiratory function disorders in clinical trials involve lower respiratory tract abnormalities (Fig. 2). Lung compliance is quantified by measuring the amount of transpulmonary pressure (mouth pressure–pleural pressure) required to achieve a given lung volume. Methodology is currently available for measuring lung compliance in rodents and non-rodents either during spontaneous breathing (dynamic lung compliance) or using a forced maneuver procedure that involves a controlled inflation and deflation of the lung and evaluating the slope of the expiratory phase of a pressure–volume loop (Diamond and O’Donnell, 1977; Costa, 1985). 5.2. Addition of investigative endpoints A future direction for respiratory safety pharmacology should also include on a case by case basis the use of methodologies or endpoints that provide mechanistic insight or help identify new

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potential drug targets. Although respiratory rate and tidal volume can detect changes in pulmonary ventilation, the inclusion of additional endpoints such as inspiratory time and flow, expiratory time and flow and apneic time can expand the amount of information obtained by providing mechanistic insight. For example, a selective increase in inspiratory time or decrease in mean inspiratory flow (tidal volume/inspiratory time) is indicative of a decrease in respiratory drive, (Remmers, 1976) while a selective increase in expiratory time or decrease in expiratory flow can be indicative of airway obstruction (Glaab et al., 2002). In addition, the presence of an endinspiratory pause or end-expiratory pause has been shown to be indicative of upper airway sensory and lower airway irritant receptor activation, respectively (Ferguson et al., 1986). Such endpoints would be useful for detecting irritation associated with an inhaled drug. Apneic time is the time between breaths and can be used for assessing breathing instability, which is especially important during the sleep state where it is used in clinical studies to identify and grade sleep disordered breathing. Apneic time is generally not considered a standard endpoint in respiratory safety pharmacology studies. However, understanding the potential effects of drugs on apneic time may be important since factors that enhance ventilatory instabilities and apneic time in the sleep state have been associated with death in children and adults (Thach, 2005; Gami et al., 2005). Sleep apnea is estimated to be present in approximately 2–10% of adults (Leger et al., 2012) and in 23–62% of the elderly (>65 years of age) (Mayson et al., 2012) and has become a major health concern in the respiratory medical community by its association with the development of systemic hypertension, pulmonary hypertension, stroke, cardiac arrhythmia, Type II diabetes, cancer and cognitive dysfunction (Benjamin and Lewis, 2008; Kohli et al., 2013). Furthermore, respiratory depressant drugs including phenothiazines and opioids are known to both induce sleep apnea and exacerbate existing sleep apnea (Kahn et al., 1985; Farney et al., 2003) Thus, when a drug treatment produces evidence of respiratory depression, the inclusion of apneic time and continuous monitoring of ventilation over a 24-h cycle would be useful for investigating a potential new target in respiratory safety pharmacology. Methods for continuous monitoring respiratory parameters over a complete diurnal cycle (24 h) in animal models currently exist. A method using inductive straps placed around the thorax and abdomen (respiratory inductive plethysmography) is currently available for obtaining ventilatory parameters in the dog (Murphy et al., 2010) and monkey (Ingram-Ross et al., 2012). A method for measuring ventilatory changes using thoracic impedance measurements also exists for dogs, (Kearney et al., 2010) while whole body plethysmography has been successfully used in dogs (Talavera et al., 2006), rodents (Schierok et al., 2000) and monkeys (Iizuka et al., 2010). Respiratory inductive plethysmography has the advantage of also providing a measure of airway obstruction that can be obtained by analyzing shifts in the timing of the thoracic and abdominal movements (phase angle) (Tobin et al., 1987). Although the measurement of lung compliance can help in the early identification of lower respiratory tract injury, it does not provide a complete measure of the functional consequences. To better characterize the functional consequences of these changes, the impact on blood gas diffusion should be considered. Comparing the relative changes in the partial pressures of the arterial O2 (PaO2) and CO2 (PaCO2) is one method for detecting injury that would hinder the diffusion of gases between the alveoli and the pulmonary arterioles as would be caused by interstitial or intraalveolar accumulation of fluid (edema) or cells (pneumonitis), reduction in alveolar ventilation by small airway or alveolar obstruction (broncholitis obliterans) or the reduction in alveolar blood flow (shunting). A reduction in gas diffusion would be indicated by a selective decrease in PaO2 relative to PaCO2, and is


generally quantified by calculating the ratio of PaO2/PaCO2. A reduction in gas diffusion capacity can also be measured as an increase in the ratio of inhaled O2 (FiO2) to PaO2 or a reduction in carbon monoxide diffusion capacity (DLCO) (Kialouama et al., 2011; Qureshi, 2011). Thus, the addition of a measure of blood gas diffusion capacity would be of value when an effect on lung compliance has been detected. 5.3. Use of stimulation models The use of stimulation models should be considered in respiratory safety pharmacology studies when there is a need for a more sensitive measure of effect or the need to quantify the loss of functional reserve. Quantifying the loss of functional reserve may be of value when attempting to identify the potential impact or risk of an effect in a sensitive patient population where a loss of functional reserve has been identified. Stimulation models utilize healthy animals to avoid the complications of induced disease models and use graded stimulation to allow for detection and quantification of the loss of functional reserve. Stimulation models used to detect the loss of ventilatory reserve include the use a graded exercise (running) to assess a decrease in maximal ventilation or gas exchange (Kittleson et al., 1996; Bouitbir et al., 2011) and the use of inhaled air mixtures with elevated CO2 or reduced O2 to evaluate the change in maximal ventilatory response or respiratory drive (Bellville and Seed, 1960; Weil and Zwillich, 1976; Schaper et al., 1985; Howell, 1993). By quantifying the loss of functional reserve, the potential impact on morbidity and mortality in human patients with a known loss of functional reserve could be evaluated. Similarly, stimulation models can be used to evaluate the loss of functional reserve for lung airflow and compliance. One established model in anesthetized rodents involves the use of a pulmonary forced maneuvers procedure, which involves the controlled maximal inflation and deflation of the lung and the simultaneous measurement of flow, volume and transpulmonary pressure (Diamond and O’Donnell, 1977; Costa, 1985). One maneuver involves inflation of the lung to a maximum volume (inspiratory capacity) and then rapidly deflating the lung by connecting the trachea to a negative pressure reservoir while recording lung airflow and volume. This procedure can be used to calculate flow endpoints such as forced expiratory volume (FEV) at specific expiratory times, peak expiratory flow (PEF), and flow at 25% and 75% of forced vital capacity (FEF25-75). By measuring the change from a maximal or forced (stimulated) flow, the loss of functional reserve for lung airflow can be determined. A maneuver involving a slow inflation to inspiratory capacity followed by a slow deflation, and an evaluation of the slope of the expiratory phase of the pressure–volume loop, can also be performed by this procedure to calculate a static or quasi-static lung compliance (Diamond and O’Donnell, 1977; Costa, 1985). By measuring compliance under forced (stimulated) volume and pressure conditions, a loss of reserve can be determined. 6. Conclusion To enhance the ability of respiratory safety pharmacology studies to detect and characterize drug-induced effects on respiratory function, it is recommended that future directions for respiratory safety pharmacology should (1) include sensitive methodologies for detecting both ventilatory alterations and lung dysfunction, (2) consider the use of additional investigative measurement endpoints when needed to help further characterize and/or provide mechanistic insight for drug-induced respiratory functional effects, and (3) consider the use of respiratory stimulation models when needed to increase sensitivity of detection or to quantify loss of functional reserve.


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Respiratory safety pharmacology - current practice and future directions.

Current practice in respiratory safety pharmacology generally follows the guidance provided by the ICH document S7A and, in general, focuses on measur...
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