First clinical experience with TRV027: Pharmacokinetics and pharmacodynamics in healthy volunteers

Journal of Clinical Pharmacology

Volumn 53, Issue 9, 2013, Pages 892-899

  Soergel, David G ^a   Subach, Ruth Ann ^a   Cowan, Conrad L ^a   Violin, Jonathan D ^a   Lark, Michael W ^a  

^a TREVENA INC   (United States)

Author keywords

Acute heart failure; First time in human; Pharmacodynamics; Pharmacokinetics; TRV027

Indexed keywords

ANGIOTENSIN RECEPTOR ANTAGONIST; CHLORIDE; CREATININE; PLACEBO; POLYPEPTIDE; POTASSIUM; SODIUM; TRV 027; UNCLASSIFIED DRUG;

ACUTE HEART FAILURE; ADULT; AREA UNDER THE CURVE; ARTICLE; BLOOD PRESSURE REGULATION; BODY TEMPERATURE; BREATHING RATE; CHLORIDE URINE LEVEL; CONTINUOUS INFUSION; CONTROLLED STUDY; CREATININE CLEARANCE; CROSSOVER PROCEDURE; DIASTOLIC BLOOD PRESSURE; DIZZINESS; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG HALF LIFE; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; ELECTROCARDIOGRAM; ELECTROLYTE URINE LEVEL; FEMALE; HEART RATE; HUMAN; LABORATORY TEST; MALE; MAXIMUM PLASMA CONCENTRATION; MEAN ARTERIAL PRESSURE; NORMAL HUMAN; PARESTHESIA; PATHOPHYSIOLOGY; PLASMA RENIN ACTIVITY; POTASSIUM URINE LEVEL; RANDOMIZED CONTROLLED TRIAL; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; SIDE EFFECT; SODIUM RESTRICTION; SODIUM URINE LEVEL; SYSTOLIC BLOOD PRESSURE; TELEMETRY;

ACUTE HEART FAILURE; FIRST-TIME-IN-HUMAN; PHARMACODYNAMICS; PHARMACOKINETICS; TRV027;

ADULT; ANGIOTENSIN II TYPE 1 RECEPTOR BLOCKERS; ANTIHYPERTENSIVE AGENTS; BLOOD PRESSURE; CROSS-OVER STUDIES; DIET, SODIUM-RESTRICTED; DOUBLE-BLIND METHOD; FEMALE; HUMANS; MALE; MIDDLE AGED; OLIGOPEPTIDES; RENIN;

EID: 84885056564     PISSN: 00912700     EISSN: 15524604     Source Type: Journal    
DOI: 10.1002/jcph.111     Document Type: Article

References (28)

1. Johnson W, Omland T, Hall C, et al. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol. 2002;39 (10):1623-1629. (Pubitemid 34494285)
2. Bishu K, Deswal A, Chen HH, et al. Biomarkers in acutely decompensated heart failure with preserved or reduced ejection fraction. Am Heart J. 2012;164(5):763-770; e63.
3. Onwuanyi A, Taylor M. Acute decompensated heart failure: pathophysiology and treatment. Am J Cardiol. 2007;99(6B):25D-30D.
4. McElroy PA, Shroff SG, Weber KT. Pathophysiology of the failing heart. Cardiol Clin. 1989;7(1):25-37. (Pubitemid 19070271)
5. Verdejo HE, del Campo A, Troncoso R, et al. Mitochondria, myocardial remodeling, and cardiovascular disease. Curr Hypertens Rep. 2012;14(6):532-539.
6. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med. 2007;49(5):627-669. (Pubitemid 46601692)
7. Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992;327(10):678-684.
8. Crozier I, Ikram H, Awan N, et al. Losartan in heart failure. Hemodynamic effects and tolerability. Losartan Hemodynamic Study Group. Circulation. 1995;91(3):691-697.
9. Dzau VJ. Cardiac renin-angiotensin system. Molecular and functional aspects. Am J Med. 1988;84(3A):22-27.
10. Guthrie GP Jr. Angiotensin receptors: physiology and pharmacology. Clin Cardiol. 1995;18(6 Suppl 3):III 29-34.
11. Rajagopal K, Whalen EJ, Violin JD, et al. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1Areceptor in isolated cardiac myocytes. Proc Natl Acad Sci USA. 2006;103(44):16284-16289. (Pubitemid 44715188)
12. Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev. 2000;52(4):639-672.
13. Ahn S, Kim J, Hara MR, Ren XR, Lefkowitz RJ. {beta}-Arrestin-2 mediates anti-apoptotic signaling through regulation of BAD phosphorylation. J Biol Chem. 2009;284(13):8855-8865.
14. Ahn S, Nelson CD, Garrison TR, Miller WE, Lefkowitz RJ. Desensitization, internalization, and signaling functions of betaarrestins demonstrated by RNA interference. Proc Natl Acad Sci USA. 2003;100(4):1740-1744. (Pubitemid 36254518)
15. DeWire SM, Violin JD. Biased ligands for better cardiovascular drugs: dissecting G-protein-coupled receptor pharmacology. Circ Res. 2011;109(2):205-216.
16. Aplin M, Christensen GL, Hansen JL. Pharmacologic perspectives of functional selectivity by the angiotensin II type 1 receptor. Trends Cardiovasc Med. 2008;18(8):305-312.
17. Violin JD, DeWire SM, Yamashita D, et al. Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther. 2010;335(3):572-579.
18. Kim KS, Abraham D, Williams B, Violin JD, Mao L, Rockman HA. Beta-arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury. Am J Physiol Heart Circ Physiol. 2012;303(8): H1001-H1010.
19. Boerrigter G, Lark MW, Whalen EJ, Soergel DG, Violin JD, Burnett JC Jr. Cardiorenal actions of TRV120027, a novel ss-arrestin-biased ligand at the angiotensin II type I receptor, in healthy and heart failure canines: A novel therapeutic strategy for acute heart failure. Circ Heart Fail. 2011;4(6):770-778.
20. Boerrigter G, Soergel DG, Violin JD, Lark MW, Burnett JC Jr. TRV120027, a novel beta-arrestin biased ligand at the angiotensin II type I receptor, unloads the heart and maintains renal function when added to furosemide in experimental heart failure. Circ Heart Fail. 2012;5(5):627-634.
21. Rogacz S, Williams GH, Hollenberg NK. Time course of enhanced adrenal responsiveness to angiotensin on a low salt diet. Hypertension. 1990;15(4):376-380. (Pubitemid 20137591)
22. Burnier M, Rutschmann B, Nussberger J, et al. Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects. Hypertension. 1993;22(3):339-347. (Pubitemid 23254082)
23. Hall JE. The renin-angiotensin system: renal actions and blood pressure regulation. Compr Ther. 1991;17(5):8-17.
24. Wexler RR, Carini DJ, Duncia JV, et al. Rationale for the chemical development of angiotensin II receptor antagonists. Am J Hypertens. 1992;5(12 Pt 2):209S-220S. (Pubitemid 23076897)
25. Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J. 1987;57(1):17-22. (Pubitemid 17216948)
26. MacFadyen RJ, Elliott HL, Meredith PA, Reid JL. Haemodynamic and hormonal responses to oral enalapril in salt depleted normotensive man. Br J Clin Pharmacol. 1993;35(3):299-301. (Pubitemid 23074056)
27. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147(2):331- 338. (Pubitemid 38176835)
28. Felker GM, O'Connor CM, Braunwald E. Loop diuretics in acute decompensated heart failure: necessary? Evil? A necessary evil? Circ Heart Fail. 2009;2(1):56-62.