Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point Emma C.Y. Hilton, PhD, Paul G.

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Pharmacodynamic modeling of cough responses to capsaicin inhalation calls into question the utility of the C5 end point Emma C.Y. Hilton, PhD, Paul G. Baverel, PhD, Ashley Woodcock, MD, Piet H. Van Der Graaf, PhD, Jaclyn A. Smith, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 4, Pages 847-855.e5 (October 2013) DOI: 10.1016/j.jaci.2013.04.042 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Challenge designs. A, Challenge 1: increasing doubling dose challenge. In this example the maximum tolerated dose inhaled was 31.3 μmol/L (red bars), and therefore the white bars represent the higher doses not inhaled. B, Example of challenge 2: randomized order of doses inhaled in challenge 1. Each bar represents a single-breath inhalation of capsaicin, and the gaps represent placebo inhalations. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, Average capsaicin dose-response curves of model predictions for patients with CC and subjects in the HV/asthmatic patient group (A/HV). B, Average capsaicin dose-response curves of model predictions for male and female patients with CC and subjects in the HV/A group. Model predictions of cough frequency are averaged at each dose across both challenge designs. Mean log(ED50) estimates are indicated by vertical lines. Standard cough challenge end points, C5 and C2, are indicated by horizontal dotted lines. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Box and whisker plot of individual Emax and log(ED50) estimates stratified by disease group and sex. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Average dose-response curves of model predictions for female patients with CC and HVs/asthmatic patients (HV/A) for challenges 1 and 2. Log(ED50) estimates are indicated. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Average capsaicin dose-response curves for experimental data (bars) and individual model predictions (lines) for patients with CC and HVs/asthmatic patients (HV/A). Model predictions of cough frequency are averaged at each dose across both challenge designs after adjusting for tachyphylaxis. Standard cough challenge end points, C5 and C2, are indicated by horizontal dotted lines. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Correlation of Emax (A) and ED50 (B) values with 24-hour spontaneous cough frequency. ED50 value and cough frequency are plotted on log10 scales. Note the extensive overlap in individual ED50 values in HVs and patients with CC but not with Emax values. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 This figure shows the sigmoid curve representing equation 2, and the effect on this curve of increases in the intercept E0 (A), the slope γ (B), the Emax value (C), and the ED50 value (D). Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Calculation of the j-value for challenge 1 (A) and an example for challenge 2 (B). Each bar represents a single-breath inhalation of capsaicin. A dose-dependent tachyphylaxis effect was estimated according to j, which was defined as the number of preceding capsaicin doses that were equal or higher (indicated above the bars). Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A-C, Mean number of coughs with each inhalation for challenge 1 in all patient groups, demonstrating the effect of tachyphylaxis when repeated inhalations of the same concentration of capsaicin are inhaled. The numbers above each concentration represent the number of subjects inhaling each concentration. Journal of Allergy and Clinical Immunology 2013 132, 847-855.e5DOI: (10.1016/j.jaci.2013.04.042) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions