Elsevier

Respiratory Medicine

Volume 103, Issue 8, August 2009, Pages 1159-1166
Respiratory Medicine

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

https://doi.org/10.1016/j.rmed.2009.02.011Get rights and content
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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 600 mcg of TPI 1020 (n = 13) or 400 mcg of budesonide (n = 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 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 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 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

Abbreviations

ACSS
asthma control scoring system
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood counts
Cmax
maximal concentration
COPD
chronic obstructive pulmonary disease
CRP
C-reactive protein
ECG
electrocardiograms
eNO
exhaled nitric oxide
FEV1
forced expiratory volume in 1 s
ITT
intent to treat
PEF
peak expiratory flow
LPS
lipopolysaccharide
NO
nitric oxide
PC20
provocative concentration that causes a 20% fall
PD
pharmacodynamic
PK
pharmacokinetic
ppm
parts per million
QTc
QT interval corrected for rate
SD
standard deviation
SE
standard error
SEM
standard error of the mean
Tmax
time at maximal concentration
UFC
urinary free cortisol

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