Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 4; pp. 847 - 855.e5
• Main Authors: Hilton, Emma C.Y., Baverel, Paul G., Woodcock, Ashley, Van Der Graaf, Piet H., Smith, Jaclyn A.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.10.2013; Elsevier; Elsevier Limited
• Subjects: Administration, Inhalation; Adult; Aged; Allergy and Immunology; Antitussive Agents - administration & dosage; Anxiety; Asthma - drug therapy; Biological and medical sciences; Body mass index; breathing; Capsaicin; Capsaicin - administration & dosage; challenge; Chronic Disease; cough; Cough - chemically induced; Cough - drug therapy; dose response; Dose-Response Relationship, Drug; Estimates; Female; females; Fundamental and applied biological sciences. Psychology; Fundamental immunology; human; Humans; Immunopathology; Male; males; Medical sciences; Middle Aged; nonlinear; Patients; Pneumology; reflex; Respiratory system : syndromes and miscellaneous diseases; response; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; sensitivity; Treatment Outcome; volunteers; CC; Capsaicin; reflex; TRPV1; nonlinear; cough; HV; C2; C5; FVC; response; challenge; model; ED50; sensitivity; human; Emax; Transient receptor potential vanilloid 1; Forced vital capacity; Capsaicin dose inducing half-maximal response; E max; ED 50; Concentration of capsaicin inducing at least 2 coughs; Chronic cough; Maximum cough response evoked by any concentration of capsaicin; Concentration of capsaicin inducing at least 5 coughs; Healthy volunteer; Human; Reflex; Immunopathology; Pharmacodynamics; Modeling; Biological activity; Cough; Inhalation; Sensitivity; Immunology; Models; ED; E(max)
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.04.042

Inhaled capsaicin elicits cough reproducibly in human subjects and is widely used in the study of cough and antitussive therapies. However, the traditional end points C2 and C5 (the concentrations of capsaicin inducing at least 2 or 5 coughs, respectively) display extensive overlap between health and disease and therefore might not best reflect clinically relevant mechanisms. We sought to investigate capsaicin dose responses in different disease groups. Two novel capsaicin cough challenges were compared in patients with chronic cough (CC; n = 20), asthmatic patients (n = 18), and healthy volunteers (HVs; n = 20). Increasing doubling doses of capsaicin (0.48-1000 μmol/L, 4 inhalations per dose) were administered in challenge 1, whereas the order of the doses was randomized in challenge 2. A nonlinear mixed-effects model compared dose-response parameters by disease group and sex. Parameters were also correlated with objective cough frequency. The model classified subjects based on maximum cough response evoked by any concentration of capsaicin (Emax) and the capsaicin dose inducing half-maximal response (ED50). HVs and asthmatic patients were not statistically different for either parameter and therefore combined for analysis (mean ED50, 38.6 μmol/L [relative SE, 28%]; mean Emax, 4.5 coughs [relative SE, 11%]). Compared with HVs/asthmatic patients, patients with CC had lower ED50 values (14.7 μmol/L [relative SE, 28%], P = .008) and higher Emax values (8.6 coughs [relative SE, 11%], P < .0001). Emax values highly correlated with 24-hour cough frequency (r = 0.71, P < .001) and were 37% higher in female compared with male subjects, regardless of disease group (P < .001). Nonlinear mixed-effects modeling demonstrates that maximal capsaicin cough responses better discriminate health from disease and predict spontaneous cough frequency and therefore provide important insights into the mechanisms underlying CC.