Safety, pharmacodynamics and pharmacokinetics of TPI 1020 in smokers with asthma

Received 9 September 2008; accepted 15 February 2009. published online 16 March 2009.

Summary

Background

TPI 1020 is a novel compound with potential for anti-neutrophil effects. TPI 1020 exerts its effects by a dual mechanism of action involving corticosteroid activity and controlled donation of nitric oxide.

Objectives

We assessed the safety, pharmacodynamic and pharmacokinetic activity of ascending doses of TPI 1020 compared to budesonide in asthma.

Methods

Smokers with mild asthma (n=27) were randomized to receive either 600mcg of TPI 1020 (n=13) or 400mcg of budesonide (n=14) bid for 2weeks followed by 1200 and 800mcg bid, respectively, for an additional week.

Result

There was no serious adverse event and all but one adverse event were mild or moderate (severe headache with budesonide). Patients receiving TPI 1020 reported three-fold fewer treatment-emergent AEs (n=13) than those receiving budesonide (n=39). TPI 1020 had similar effects as budesonide on FEV1, PEF, rescue medication, asthma scoring system, methacholine response, sputum eosinophils and exhaled NO. Sputum neutrophils (%) tended to decrease more with TPI 1020 (32.6% decrease versus 3.7% increase for budesonide); the decrease occurring only in patients with high neutrophils at baseline. A significant difference favoring TPI 1020 was noted for CRP. Budesonide caused a statistically significant decrease in 24h urinary free cortisol over 22days (median of 4.4–2.8mcg/ml, p=0.01) whereas TPI 1020 had no such effect (4.4–5.8mcg/ml), suggesting lower systemic corticosteroid exposure following TPI 1020 treatment.

Conclusion

TPI 1020 appears safe in asthmatic smokers and warrants further investigation in respiratory conditions.

Keywords: Airway inflammation, Asthma/drug therapy, Nitric oxide, Neutrophils

a Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Québec, QC G1V 4G5, Canada

b Hôpital du Sacré-Cœur de Montréal, Service de Pneumologie, Université de Montréal, Montréal, QC H4J 1C5, Canada

c Department of Medicine, McMaster University, Medical Center, Hamilton, ON L8N 3Z5, Canada

d Respiratory Division of the McGill University Health Centre, Montreal, QC H2X 2P4, Canada

e Asthma Research Unit, Clinical Research Centre, Kingston General Hospital, Division of Respirology, Kingston, ON K7L 1O6, Canada

f Centre de Recherche Interdisciplinaire en Réadaptation du Montréal Métropolitain, Jewish Rehabilitation Hospital, Laval, QC H7V 3Y7, Canada

g Topigen Pharmaceuticals, Montreal, QC H1Y 3N1, Canada

h University of Montreal and Topigen Pharmaceuticals, Montreal, QC H1Y 3N1, Canada

Corresponding author. Research & Development, Topigen Pharmaceuticals Inc., 4050 Molson Street, Room 300, Montreal, QC H1Y 3N1, Canada. Tel.: +1 514 868 0077; fax: +1 514 525 9328.

Corresponding author. Hôpital Laval, 2725 chemin Sainte-Foy, Quebec, QC G1V 4G5, Canada. Tel.: +1 418 656 4747; fax: +1 418 656 4762.

PII: S0954-6111(09)00063-8

doi:10.1016/j.rmed.2009.02.011

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