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

AbstractBACKGROUND:
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 FEV(1), 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.
AuthorsLouis-Philippe Boulet, Catherine Lemière, Gail Gauvreau, Ron Olivenstein, Diane Lougheed, Bruno Paradis, Paul O'Byrne, René Pageau, Paolo M Renzi
JournalRespiratory medicine (Respir Med) Vol. 103 Issue 8 Pg. 1159-66 (Aug 2009) ISSN: 1532-3064 [Electronic] England
PMID19286361 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents
  • NCX 1020
  • Nitric Oxide
  • Budesonide
Topics
  • Adolescent
  • Adult
  • Aged
  • Anti-Inflammatory Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Asthma (drug therapy)
  • Budesonide (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Forced Expiratory Volume (drug effects)
  • Humans
  • Male
  • Middle Aged
  • Neutrophil Activation (drug effects)
  • Nitric Oxide (metabolism)
  • Sputum (cytology)
  • Treatment Outcome
  • Young Adult

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