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

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 600 mcg of TPI 1020 (n = 13) or 400 mcg of budesonide In = 14) bid for 2 weeks followed by 1200 and 800 mcg bid, respectively, for an additional week. Result: There was no serious adverse event and at( 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 24 h urinary free cortisol over 22 days (median of 4.4-2.8 mcg/ml, p = 0.01) whereas TPI 1020 had no such effect (4.4-5.8 mcg/ml), suggesting tower systemic corticosteroid exposure following TPI 1020 treatment. Conclusion: TPI 1020 appears safe in asthmatic smokers and warrants further investigation in respiratory conditions. (C) 2009 Elsevier Ltd. All rights reserved.