A First-in-Patient, Multicenter, Double-Blind, 2-Arm, Placebo-Controlled, Randomized Safety and Tolerability Study of a Novel Oral Drug Candidate, CTP-499, in Chronic Kidney Disease

Clinical Pharmacology in Drug Development

Volumn 5, Issue 4, 2016, Pages 314-325

  Sabounjian, LuAnn ^a   Graham, Philip ^a   Wu, Lijun ^a   Braman, Virginia ^a   Cheng, Changfu ^a   Liu, Julie ^a   Shipley, James ^a   Neutel, Joel ^b   Dao, Michael ^c  

^a Drug Metabolism and Pharmacokinetics   (United States)

^b Orange County Research Center   (United States)

^c SC Clinical Research   (United States)

Author keywords

chronic kidney disease; CTP 499; deuterium; pharmacokinetics

Indexed keywords

C REACTIVE PROTEIN; CTP 449; HEMOGLOBIN; INTERLEUKIN 6; MONOCYTE CHEMOTACTIC PROTEIN 1; PHOSPHODIESTERASE INHIBITOR; PLACEBO; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADULT; AGED; AREA UNDER THE CURVE; ARTICLE; BLOOD ANALYSIS; CHRONIC KIDNEY DISEASE; CLINICAL ARTICLE; CONTROLLED STUDY; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG DOSE TITRATION; DRUG HALF LIFE; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG URINE LEVEL; DYSPEPSIA; EDEMA; FEMALE; FIRST IN HUMAN STUDY; GLOMERULUS FILTRATION RATE; GOUT; HEADACHE; HEMORRHOID; HUMAN; MALE; MAXIMUM PLASMA CONCENTRATION; MULTICENTER STUDY; NAUSEA; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SKIN ULCER; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION; TREATMENT OUTCOME; UNITED STATES; VOMITING;

EID: 84975316780     PISSN: 2160763X     EISSN: 21607648     Source Type: Journal    
DOI: 10.1002/cpdd.241     Document Type: Article

References (32)

1. Collins AJ, Foley RN, Chavers B, et al. US Renal Data System 2013 annual data report. Am J Kidney Dis. http://www.usrds.org/2014/view/Default.aspx. Accessed June 5, 2014.
2. Jha V, Wang A Y-M, Wang H. The impact of CKD identification in large countries: the burden of the illness. Nephrol Dial Transplant. 2012;27(suppl 3):iii32–iii38.
3. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.
4. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49(2 Suppl 2):S12–S154.
5. Buse JB, Ginsberg HN, Bakris GL et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115(1):114–126.
6. American Diabetes Association. Standards of medical care in diabetes — 2011. Diabetes Care. 2011;34(suppl 1):S11–S61.
7. Levey AS, Cattran D, Friedman A, et al. Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2009;54(2):205–226.
8. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis. 2012;60(5):850–886.
9. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456–1462.
10. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860.
11. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–869.
12. Stevens LA, Greene T, Levey AS. Surrogate end points for clinical trial of kidney disease. Clin J Am Soc Nephrol. 2006;1(4):874–884.
13. Quiroga B, Arroyo D, de Arriba G. Present and future in the treatment of diabetic kidney disease. J Diabetes Res. 2015;2015:801348.
14. Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, Abdollahi M. A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci. 2011;14(1):128–137.
15. Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol. 2008;19(3):433–442.
16. Tang S, Bridson G, Ke J, et al. Quantitative analyses of CTP-499 and five major metabolites by core-structure analysis. J Chromatogr B Analyt Technol Biomed Life Sci. 2014;963:1–9.
17. Gant TG, Using deuterium in drug discovery: leaving the label in the drug. J Med Chem. 2014;57(9):3595
18. Parasrampuria D, Braman V, Cheng C, Grotbeck B, et al. First human exposure suggests a unique metabolic profile with multiple active species for CTP-499, a novel agent for treatment of chronic kidney disease. ASN Poster 2011 THPO358.
19. Harbeson S, Tung R. Deuterium Medicinal Chemistry: a new approach to drug discovery and development, MedChem News 2014, No. 2, 8–22.
20. Lin SL, Chaing WC, Chen YM, et al. Pentoxifylline: a potential therapy for chronic kidney disease. Nephrology. 2004;9:198–204
21. Aslanian A, Hogan K, West K, Bridson G, Wu L. CTP-499, a novel drug for the treatment of chronic kidney disease, ameliorates renal fibrosis and inflammation in vivo. ASN 2012 Poster.
22. Aslanian A, Hogan K, Qin S, et al. CTP-499, a novel drug for the potential treatment of chronic kidney disease, has anti-fibrotic, anti-inflammatory, and anti-oxidative activities with in vivo efficacy. ASN 2011 Poster.
23. Ghorbani A, Omidvar B, Beladi-Mousavi SS, Lak E, Vaziri S. The effect of pentoxifylline on reduction of proteinuria among patients with type 2 diabetes under blockade of angiotensin system: a double blind and randomized clinical trial. Nefrologia. 2012;32(6):790–796.
24. Roozbeh J, Banihashemi MA, Ghezlou M, et al. Captopril and combination therapy of captopril and pentoxifylline in reducing proteinuria in diabetic nephropathy. Ren Fail. 2010;32(2):172–178.
25. Harmankaya O, Seber S, Yilmaz M. Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients. Ren Fail. 2003;25(3):465–470.
26. Rodriguez-Moran M, Gonzalez-Gonzalez G, Bermudez-Barba MV, et al. Effects of pentoxifylline on the urinary protein excretion profile of type 2 diabetic patients with microproteinuria: a double-blind, placebo-controlled randomized trial. Clin Nephrol. 2006;66(1):3–10.
27. Lin SL, Chen YM, Chiang WC, Wu KD, Tsai TJ. Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12-month randomized trial. Am J Kidney Dis. 2008;52(3):464–474.
28. Perkins RM, Aboudara MC, Uy AL, Olson SW, Cushner HM, Yuan CM. Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis. 2009;53(4):606–616.
29. Navarro-Gonzalez J, Mora-Fernandez C, Muros de Fuentes M, et al. Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: the PREDIAN Trial. J Am Soc Nephrol. 2015; 26: 220–229.
30. Braman V, Graham P, Cheng C, et al. A randomized phase 1 evaluation of CTP-499, a novel deuterium-containing drug candidate for diabetic nephropathy. Clinical Pharm in Drug Dev. 2013;2(1):53–66.
31. Fantin M, Quintieri L, Kusz E, et al. Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties. Eur J Pharmacol. 2006;535(1-3):301–309.
32. Paap CM, Simpson KS, Horton MW, Schaefer KL, Lassman HB, Sack MR. Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency. Ann Pharmacother. 1996;30(7-8):724–729.