Evaluation of Safety of a Newly Formulated Pirfenidone in Chronic Kidney Disease: A Non-Randomized Pilot Study in Mexican Patients
Main Article Content
Keywords
Chronic Kidney Disease, glomerular filtration rate, prolonged-released Pirfenidone.
Abstract
The aim of this pilot clinical trial was to evaluate the safety of a new formulation of prolonged-release Pirfenidone (PR-PFD) in chronic kidney disease (CKD), specifically focal and segmental glomerular hyalinization (FSGH). Open-label, pilot, nonrandomized trial. Eighteen patients previously diagnosed with CKD stages 1– 5 according to “Kidney Disease: Improving Global Outcomes” were enrolled in the study. Target dos-age of PFD was 1200 mg twice a day in the form of prolonged-release tablets to reach a full dosage of 2400 mg daily. Clinical trial was carried out for 60 months to evaluate the safety and efficacy of a newly formulated PR-PFD in patients with CKD. After the treatment for 60 months, it was found that PR-PFD kept renal function from declining significantly in CKD patients, as the glomerular filtration rate (GFR) showed only minimal variations throughout the study. Estimated glomerular filtration rate (eGFR) showed no differences at both baseline and the end points. Proteinuria improved, and creatinine, cystatin C, urea, hemoglobin and hepatic transaminases remained constant without any considerable changes across the study. Minor side effects were noticed when compared with those found in previous studies, indicating an increased tolerance to this pharmaceutical formulation of PFD. Prolonged-released PFD could be safely used as an adjuvant therapy in patients with CKD.Registry number was obtained from ClinicalTrials.gov (NCT02408744).
References
1. Carville S, Wonderling D, Stevens P; Guideline Development Group. Early identification and management of chronic kidney disease in adults: Summary of updated NICE guidance. BMJ. 2014 Jul 24;349:g4507. http://dx.doi.org/10.1136/bmj.g4507
2. Levin A, Stevens PE. Summary of KDIGO 2012 CKD guide-line: Behind the scenes, need for guidance, and a framework for moving forward. Kidney Int. 2014 Jan;85(1):49–61. http://dx.doi.org/10.1038/ki.2013.444
3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017 Jul;7(1):1–59. http://dx.doi.org/10.1016/j.kisu.2017.04.001
4. Lysaght MJ. Maintenance dialysis population dynamics: Current trends and long-term implications. J Am Soc Nephrol. 2002 Jan;13(Suppl 1): S37–40.
5. Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012 Jan 14;379(9811):165–80. http://dx.doi.org/10.1016/S0140-6736(11)60178-5
6. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of Chronic Kidney Disease in the United States. Jama. 2007 Nov 7;298(17):2038–47. http://dx.doi.org/10.1001/jama.298.17.2038
7. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease–A systematic review and meta-analysis. PLoS One. 2016 Jul 6;11(7):e0158765. http://dx.doi.org/10.1371/journal.pone.0158765
8. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296–305. http://dx.doi.org/10.1056/NEJMoa041031
9. Boor P, Ostendorf T, Floege J. Renal fibrosis: Novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol. 2010 Sep 14;6(11):643–56. http://dx.doi.org/10.1038/nrneph.2010.120
10. Liu Y. Renal fibrosis: New insights into the pathogenesis and therapeutics. KidneyInt. 2006 Jan;69(2):213–17. http://dx.doi.org/10.1038/sj.ki.5000054
11. Chatziantoniou C, Dussaule JC. Insights into the mechanisms of renal fibrosis: Is it possible to achieve regression? Am J Physiol Renal Physiol. 2005 Aug 01;289(2): F227–34. http://dx.doi.org/10.1152/ajprenal.00453.2004
12. 12. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993 Nov 11;329(20):1456–62. http://dx.doi.org/10.1056/NEJM199311113292004
13. Ljutic D, Kes P. The role of arterial hypertension in the progression of non-diabetic glomerular diseases. Nephrol Dial Transplant. 2003 Jul 01;18(Suppl 5):v28–30. http://dx.doi.org/10.1093/ndt/gfg1040
14. Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011 Jun;22(6):1144–51. http://dx.doi.org/10.1681/ASN.2010101049
15. Cho ME, Kopp JB. Pirfenidone: An anti-fibrotic therapy for progressive kidney disease. Expert Opin Investig Drugs. 2010 Jan 06;19(2):275–83. http://dx.doi.org/10.1517/13543780903501539
16. Armendariz-Borunda J, Lyra-González I, Medina-Preciado D, Gonzalez-García I, Martinez-Fong D, Miranda RA, et al. A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients. Ann Plast Surg. 2012 Jan; 68(1):22–8. http://dx.doi.org/10.1097/SAP.0b013e31821b6d08
17. Armendariz-Borunda J, Islas-Carbajal MC, Meza-García E, Rincón AR, Lucano S, Sandoval AS, et al. A pilot study in patients with established advanced liver fibrosis using pirfenidone. Gut. 2006 Oct 17;55(11):1663–5. http://dx.doi.org/10.1136/gut.2006.107136
18. Veras-Castillo ER, Cardenas-Camarena L, Lyra-Gonzalez I, Moñoz-Valle JF, Lucano-Landeros S, Guerrerosantos J, et al. Controlled clinical trial with pirfenidone in the treatment of breast capsular contracture. Ann Plast Surg. 2013 Jan;70(1): 16–22. http://dx.doi.org/10.1097/SAP.0b013e31822284f4
19. Ramachandra Rao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol. 2009 Aug;20(8):1765–75. http://dx.doi.org/10.1681/ASN.2008090931
20. Shimizu T, Kuroda T, Hata S, Fukagawa M. Margolin SB, Kurokawa K. Pirfenidone improves renal function and fibro-sis in the post-obstructed kidney. Kidney Int. 1998 Jul;54(1): 99–109. http://dx.doi.org/10.1046/j.1523-1755.1998.00962.x
21. Shihab FS, Bennett WM, Yi H, Andoh TF. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant. 2002 Feb; 2(2)111–19. http://dx.doi.org/10.1034/j.1600-6143.2002.020201.x
22. Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM, Beown L. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol. 2001 Jul;133(5):687–94. http://dx.doi.org/10.1038/sj.bjp.0704131
23. Brook NR, Waller JR, Bicknell GR, Nicholson ML. The experimental agent pirfenidone reduces profibrotic gene expression in a model of tacrolimus-induced nephrotoxicity. J Surg Res. 2005 May 15;125(2):137–43. http://dx.doi.org/10.1016/j.jss.2004.12.007
24. Leh S, Vaagnes Ø, Margolin SB, Iversen BM, Forslund T. Pirfenidone and candesartan ameliorate morphological dam-age in mild chronic anti-GBM nephritis in rats. Nephrol Dial Transplant. 2005 Jan;20(1):71–82. http://dx.doi.org/10.1093/ndt/gfh562
25. Declèves AE, Sharma K. Novel targets of antifibrotic and anti-inflammatory treatment in CKD. Nat Rev Nephrol. 2014 Mar 25;10(5):257–67. http://dx.doi.org/10.1038/nrneph.2014.31
26. Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2007 Sep;2(5):906–13. http://dx.doi.org/10.2215/CJN.01050207
27. Lancaster L, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, et al. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: Integrated analysis of cumulative data from 5 clinical trials. BMJ Open Resp Res. 2016 Jan 12;3:e000105. http://dx.doi.org/10.1136/bmjresp-2015-000105
28. Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, et al. Effect of pirfenidone on the pulmonary fibro-sis of Hermansky-Pudlak syndrome. Mol Genet Metab. 2002 Jul; 76(3):234–42. http://dx.doi.org/10.1016/S1096-7192(02)00044-6
29. Bowen JD, Maravilla K, Margolin SB. Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis. Mult Scler. 2003 Jul 01;9(3):280–3. http://dx.doi.org/10.1191/1352458503ms907oa
30. Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T. Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern Med. 2002 Dec;41(12):1118–23. http://dx.doi.org/10.2169/internalmedicine.41.1118
31. Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al. Relation between kidney function, proteinuria, and adverse outcomes. Jama. 2010 Feb 3;303(5):423–9. http://dx.doi.org/10.1001/jama.2010.39
32. Allison SJ. Proteinuria is an important indicator of adverse outcomes in CKD. Nat Rev Nephrol. 2010 Apr;6(4):187. http://dx.doi.org/10.1038/nrneph.2010.29
33. Shi S, Wu J, Chen H, Chen H, Wu J, Zeng F. Single- and multiple-dose pharmacokinetics of pirfenidone, an anti-fibrotic agent, in healthy Chinese volunteers. J Clin Pharmacol. 2007 Oct;47(10):1268–76. http://dx.doi.org/10.1177/0091270007304104
34. Ikezoe K, Handa T, Tanizawa K, Yokoi H, Kubo T, Aihara K, et al. Chronic kidney disease predicts survival in patients with idiopathic pulmonary fibrosis. Respiration. 2017;94(4):346–54. http://dx.doi.org/10.1159/000478787
2. Levin A, Stevens PE. Summary of KDIGO 2012 CKD guide-line: Behind the scenes, need for guidance, and a framework for moving forward. Kidney Int. 2014 Jan;85(1):49–61. http://dx.doi.org/10.1038/ki.2013.444
3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017 Jul;7(1):1–59. http://dx.doi.org/10.1016/j.kisu.2017.04.001
4. Lysaght MJ. Maintenance dialysis population dynamics: Current trends and long-term implications. J Am Soc Nephrol. 2002 Jan;13(Suppl 1): S37–40.
5. Levey AS, Coresh J. Chronic kidney disease. Lancet. 2012 Jan 14;379(9811):165–80. http://dx.doi.org/10.1016/S0140-6736(11)60178-5
6. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of Chronic Kidney Disease in the United States. Jama. 2007 Nov 7;298(17):2038–47. http://dx.doi.org/10.1001/jama.298.17.2038
7. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease–A systematic review and meta-analysis. PLoS One. 2016 Jul 6;11(7):e0158765. http://dx.doi.org/10.1371/journal.pone.0158765
8. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004 Sep 23;351(13):1296–305. http://dx.doi.org/10.1056/NEJMoa041031
9. Boor P, Ostendorf T, Floege J. Renal fibrosis: Novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol. 2010 Sep 14;6(11):643–56. http://dx.doi.org/10.1038/nrneph.2010.120
10. Liu Y. Renal fibrosis: New insights into the pathogenesis and therapeutics. KidneyInt. 2006 Jan;69(2):213–17. http://dx.doi.org/10.1038/sj.ki.5000054
11. Chatziantoniou C, Dussaule JC. Insights into the mechanisms of renal fibrosis: Is it possible to achieve regression? Am J Physiol Renal Physiol. 2005 Aug 01;289(2): F227–34. http://dx.doi.org/10.1152/ajprenal.00453.2004
12. 12. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993 Nov 11;329(20):1456–62. http://dx.doi.org/10.1056/NEJM199311113292004
13. Ljutic D, Kes P. The role of arterial hypertension in the progression of non-diabetic glomerular diseases. Nephrol Dial Transplant. 2003 Jul 01;18(Suppl 5):v28–30. http://dx.doi.org/10.1093/ndt/gfg1040
14. Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, et al. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011 Jun;22(6):1144–51. http://dx.doi.org/10.1681/ASN.2010101049
15. Cho ME, Kopp JB. Pirfenidone: An anti-fibrotic therapy for progressive kidney disease. Expert Opin Investig Drugs. 2010 Jan 06;19(2):275–83. http://dx.doi.org/10.1517/13543780903501539
16. Armendariz-Borunda J, Lyra-González I, Medina-Preciado D, Gonzalez-García I, Martinez-Fong D, Miranda RA, et al. A controlled clinical trial with pirfenidone in the treatment of pathological skin scarring caused by burns in pediatric patients. Ann Plast Surg. 2012 Jan; 68(1):22–8. http://dx.doi.org/10.1097/SAP.0b013e31821b6d08
17. Armendariz-Borunda J, Islas-Carbajal MC, Meza-García E, Rincón AR, Lucano S, Sandoval AS, et al. A pilot study in patients with established advanced liver fibrosis using pirfenidone. Gut. 2006 Oct 17;55(11):1663–5. http://dx.doi.org/10.1136/gut.2006.107136
18. Veras-Castillo ER, Cardenas-Camarena L, Lyra-Gonzalez I, Moñoz-Valle JF, Lucano-Landeros S, Guerrerosantos J, et al. Controlled clinical trial with pirfenidone in the treatment of breast capsular contracture. Ann Plast Surg. 2013 Jan;70(1): 16–22. http://dx.doi.org/10.1097/SAP.0b013e31822284f4
19. Ramachandra Rao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol. 2009 Aug;20(8):1765–75. http://dx.doi.org/10.1681/ASN.2008090931
20. Shimizu T, Kuroda T, Hata S, Fukagawa M. Margolin SB, Kurokawa K. Pirfenidone improves renal function and fibro-sis in the post-obstructed kidney. Kidney Int. 1998 Jul;54(1): 99–109. http://dx.doi.org/10.1046/j.1523-1755.1998.00962.x
21. Shihab FS, Bennett WM, Yi H, Andoh TF. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. Am J Transplant. 2002 Feb; 2(2)111–19. http://dx.doi.org/10.1034/j.1600-6143.2002.020201.x
22. Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM, Beown L. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol. 2001 Jul;133(5):687–94. http://dx.doi.org/10.1038/sj.bjp.0704131
23. Brook NR, Waller JR, Bicknell GR, Nicholson ML. The experimental agent pirfenidone reduces profibrotic gene expression in a model of tacrolimus-induced nephrotoxicity. J Surg Res. 2005 May 15;125(2):137–43. http://dx.doi.org/10.1016/j.jss.2004.12.007
24. Leh S, Vaagnes Ø, Margolin SB, Iversen BM, Forslund T. Pirfenidone and candesartan ameliorate morphological dam-age in mild chronic anti-GBM nephritis in rats. Nephrol Dial Transplant. 2005 Jan;20(1):71–82. http://dx.doi.org/10.1093/ndt/gfh562
25. Declèves AE, Sharma K. Novel targets of antifibrotic and anti-inflammatory treatment in CKD. Nat Rev Nephrol. 2014 Mar 25;10(5):257–67. http://dx.doi.org/10.1038/nrneph.2014.31
26. Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2007 Sep;2(5):906–13. http://dx.doi.org/10.2215/CJN.01050207
27. Lancaster L, Albera C, Bradford WZ, Costabel U, du Bois RM, Fagan EA, et al. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: Integrated analysis of cumulative data from 5 clinical trials. BMJ Open Resp Res. 2016 Jan 12;3:e000105. http://dx.doi.org/10.1136/bmjresp-2015-000105
28. Gahl WA, Brantly M, Troendle J, Avila NA, Padua A, Montalvo C, et al. Effect of pirfenidone on the pulmonary fibro-sis of Hermansky-Pudlak syndrome. Mol Genet Metab. 2002 Jul; 76(3):234–42. http://dx.doi.org/10.1016/S1096-7192(02)00044-6
29. Bowen JD, Maravilla K, Margolin SB. Open-label study of pirfenidone in patients with progressive forms of multiple sclerosis. Mult Scler. 2003 Jul 01;9(3):280–3. http://dx.doi.org/10.1191/1352458503ms907oa
30. Nagai S, Hamada K, Shigematsu M, Taniyama M, Yamauchi S, Izumi T. Open-label compassionate use one year-treatment with pirfenidone to patients with chronic pulmonary fibrosis. Intern Med. 2002 Dec;41(12):1118–23. http://dx.doi.org/10.2169/internalmedicine.41.1118
31. Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, et al. Relation between kidney function, proteinuria, and adverse outcomes. Jama. 2010 Feb 3;303(5):423–9. http://dx.doi.org/10.1001/jama.2010.39
32. Allison SJ. Proteinuria is an important indicator of adverse outcomes in CKD. Nat Rev Nephrol. 2010 Apr;6(4):187. http://dx.doi.org/10.1038/nrneph.2010.29
33. Shi S, Wu J, Chen H, Chen H, Wu J, Zeng F. Single- and multiple-dose pharmacokinetics of pirfenidone, an anti-fibrotic agent, in healthy Chinese volunteers. J Clin Pharmacol. 2007 Oct;47(10):1268–76. http://dx.doi.org/10.1177/0091270007304104
34. Ikezoe K, Handa T, Tanizawa K, Yokoi H, Kubo T, Aihara K, et al. Chronic kidney disease predicts survival in patients with idiopathic pulmonary fibrosis. Respiration. 2017;94(4):346–54. http://dx.doi.org/10.1159/000478787
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May 18, 2020
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Evaluation of Safety of a Newly Formulated Pirfenidone in Chronic Kidney Disease: A Non-Randomized Pilot Study in Mexican Patients. (2020). Journal of Renal and Hepatic Disorders, 4(1), 22-30. https://doi.org/10.15586/jrenhep.2020.61
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Original Articles Nephrology
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