A FIM study to assess safety and exposure of inhaled single doses of AP301 - A specific ENaC channel activator for the treatment of acute lung injury

Journal of Clinical Pharmacology

Volumn 54, Issue 3, 2014, Pages 341-350

  Schwameis, Richard ^a   Eder, Sandra ^a   Pietschmann, Helmut ^b   Fischer, Bernhard ^b   Mascher, Hermann ^c   Tzotzos, Susan ^b   Fischer, Hendrik ^b   Lucas, Rudolf ^d   Zeitlinger, Markus ^a   Hermann, Robert ^e  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

^b APEPTICO GmbH   (Austria)

^c Pharm analyt Labor GmbH   (Austria)

^d MEDICAL COLLEGE OF GEORGIA   (United States)

^e Clinical Research Appliance   (Germany)

Author keywords

AP301; ARDS; ENaC activator; first in man study

Indexed keywords

AP 301; EPITHELIAL SODIUM CHANNEL STIMULATING AGENT; NITRIC OXIDE; PLACEBO; UNCLASSIFIED DRUG;

ACUTE LUNG INJURY; ADULT; AREA UNDER THE CURVE; ARTICLE; BLOOD SAMPLING; BRONCHOSPASM; CLINICAL ARTICLE; CONTROLLED STUDY; COUGHING; DOUBLE BLIND PROCEDURE; DRUG EXPOSURE; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAM; HOARSENESS; HUMAN; LIMIT OF QUANTITATION; MALE; MAXIMUM PLASMA CONCENTRATION; MUCOSA INFLAMMATION; OUTCOME ASSESSMENT; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; SPIROMETRY; VITAL SIGN;

AP301; ARDS; ENAC ACTIVATOR; FIRST-IN-MAN STUDY;

ACUTE LUNG INJURY; ADMINISTRATION, INHALATION; ADULT; BLOOD PRESSURE; DOUBLE-BLIND METHOD; EPITHELIAL SODIUM CHANNELS; HUMANS; MALE; NEBULIZERS AND VAPORIZERS; NITRIC OXIDE; PEPTIDES, CYCLIC; PULSE; SPIROMETRY; YOUNG ADULT;

EID: 84898639896     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1002/jcph.203     Document Type: Article

References (29)

1. Definition Task Force ARDS, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012; 307: 2526-2533.
2. De Luca D, Piastra M, Chidini G, et al. The new "Berlin definition" of acute respiratory distress syndrome: clinical evaluation in infants and expert consensus. Intensive Care Med. 2013; 39 (Suppl 1): S197-S198.
3. Phua J, Badia JR, Adhikari NKJ, Wendel A, Lucas R., Has mortality from acute respiratory distress syndrome decreased over time ? Am J Respir Crit Care Med. 2009; 179: 220-227.
4. Lucas R, Magez S, De Leys R, et al. Mapping the lectin-like activity of tumor necrosis factor. Science. 1994; 263 (5148): 814-817. (Pubitemid 24093210)
5. Braun C, Hamacher J, Morel DR, Wendel A, Lucas R., Dichotomal role of TNF in experimental pulmonary edema reabsorption. J Immunol. 2005; 175: 3402-3408. (Pubitemid 41170563)
6. Elia N, Tapponnier M, Matthay MA, et al. Functional identification of the alveolar edema reabsorption activity of murine tumor necrosis factor-alpha. Am J Respir Crit Care Med. 2003; 168: 1043-1050. (Pubitemid 37338932)
7. Vadasz I, Schermuly RT, Ghofrani HA, et al. The lectin-like domain of TNF-a improves alveolar fluid balance in injured isolated rabbit lungs. Crit Care Med. 2008; 36: 1543-1550. (Pubitemid 351620646)
8. Xiong C, Yang G, Kumar S, et al. The lectin-like domain of TNF protects from Listeriolysin-induced hyperpermeability in human pulmonary microvascular endothelial cells-a crucial role for Protein Kinase C-alpha inhibition. Vascul Pharmacol. 2010; 52 (5-6): 207-213.
9. Hamacher J, Stammberger U, Roux J, et al. The lectin-like domain of TNF improves lung function after rat lung transplantation-potential role for a reduction in reactive oxygen species generation. Crit Care Med. 2010; 38 (3): 871-878.
10. Lucas R, Yang G, Gorshkov B, et al. Protein kinase C-α and Arginase I mediate Pneumolysin-induced pulmonary endothelial hyperpermeability. Am J Resp Cell Mol Biol. 2012; 47 (4): 445-453.
11. Berthiaume Y., Tumor necrosis factor and lung edema clearance: the tip of the iceberg ? Am J Respir Crit Care Med. 2003; 168 (9): 1022-1023. (Pubitemid 37338925)
12. Matthay MA, Berthiaume Y., Novel molecular strategy to prevent pulmonary edema. Crit Care Med. 2008; 36: 1671-1672.
13. Mora-Esteves C, Dikdan G, Koneru B., Dr. Jekyll and Mr. Hyde saga of a cytokine: the devil in the details. Crit Care Med. 2010; 38 (3): 997-998.
14. Hartmann EK, Boehme S, Duenges B, et al. An inhaled tumor necrosis factor-alpha-derived TIP peptide improves the pulmonary function in experimental lung injury. Acta Anaesthesiol Scand. 2013; 57: 334-341.
15. Tzotzos S, Fischer B, Fischer H, et al. AP301, a synthetic peptide mimicking the lectin-like domain of TNF, enhances amiloride-sensitive Na; current in primary dog, pig and rat alveolar type II cells. Pulm Pharmacol Ther. 2013; Jan 9. pii: S1094-5539(13)00003-5. doi: 10.1016/j.pupt.2012.12.011 [Epub ahead of print].
16. Lee JW, Fang X, Dolganov G, et al. Acute lung injury edema fluid decreases net fluid transport across human alveolar epithelial type II cells. J Biol Chem. 2007; 282 (33): 24109-24119. (Pubitemid 47328055)
17. EMA (CHMP). Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products. EMEA-CHMP/SWP/28367/07, 19th July 2007.
18. U.S. Department of Health and Human Services, Food and Drug Administration, Center for drug Evaluation and Research (CDER). Guidance for industry "estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers". http://www.fda.gov/ downloads/Drugs/Guidances/UCM078932.pdf. July 2005.
19. Wolff RK, Dorato MA., Toxicologic testing of inhaled pharmaceutical aerosols. Crit Rev Toxicol. 1993; 23: 343-369. (Pubitemid 24010013)
20. Lewis TR, Morrow PE, McClellan RO, et al. Establishing aerosol exposure concentrations for inhalation toxicity studies. Toxicol Appl Pharmacol. 1989; 99: 377-383. (Pubitemid 19189752)
21. American Thoracic Society Documents. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005; 171: 912-930.
22. ICH. ICH harmonised tripartite guideline E14. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. http://www.ich.org/fileadmin/Public-Web-Site/ICH-Products/Guidelines/ Efficacy/E14/E14-Guideline.pdf. October 2005.
23. Mascher D, Tscherwenka W, Mascher H, Fischer B., Sensitive determination of the peptide AP301-a motif of TNF-α-from human plasma using HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2012; 908: 18-22.
24. Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006; 355: 1018-1028. (Pubitemid 44343545)
25. Dresser R., First-in-human trial participants: not a vulnerable population, but vulnerable nonetheless. J Law Med Ethics. 2009 37: 38-50.
26. Dayan CM, Wraith DC., Preparing for first-in-man studies: the challenges for translational immunology post-TGN1412. Clin Exp Immunol. 2008; 151: 231-234.
27. Jones KM, Liao E, Hohneker K, et al. Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis. Pharmacotherapy. 1997; 17: 263-270. (Pubitemid 27133351)
28. Knox AJ, Britton JR, Tattersfield AE., Effect of sodium-transport inhibitors on bronchial reactivity in vivo. Clin Sci (Lond). 1990; 79: 325-330. (Pubitemid 20331468)
29. Penel N, Kramar A., What does a modified-Fibonacci dose-escalation actually correspond to ? BMC Med Res Methodol. 2012; 12: 103-107.