Use of narrow therapeutic index drugs in organ transplantation
Main Article Content
Abstract
A safe and effective use of immunosuppressants for optimal therapeutic benefit in transplant patients is a matter of constant concern. In order to achieve a balance between safety and efficacy, a thorough understanding of the pharmacokinetics and pharmacodynamics of a drug, and tools to help maintaining target drug levels such as therapeutic drug monitoring are required. Particular concern is given to drugs with a narrow therapeutic window, such as calcineurin inhibitors. In addition, the introduction of many generic drugs with the same active ingredient under economic pressure is also a challenge for clinicians to choose. This review presents some basic concepts in using drugs with narrow therapeutic index, some properties of calcineurin inhibitors, bioequivalence requirements for safe and effective clinical use, and pointers to keep in mind when using generic drugs of calcineurin inhibitors for interchangeability and substitution in organ transplantation.
Article Details
Keywords
calcineurin inhibitors, drugs with narrow therapeutic index, therapeutic drug monitoring, bioequivalence, interchangeability and substitution of immunosuppressive drugs
References
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12. Saeki T, Ueda K, Tanigawara Y, et al. Human P-glycoprotein transports cyclosporine A and FK506. J Biol Chem. 1993;268:6077-6080.
13. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–391.
14. MacPhee IA, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant. 2004;4:914-919.
15. MacPhee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation. 2005;79:499-502.
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17. Ameyaw MM, Regateiro F, Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001;11:217–221.
18. Mai I, Stömer E, Goldammer M, et al. MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol. 2003;43:1101–1107.
19. Zhang X, Liu Z, Zheng J, et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant. 2005;19:638-643.
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28. Tariq Ahmad. Pharmacological classification of drugs. 1st ed. Dept. of Pharmacy, Univ of Lahore.
29. Maureen Burns. Management of narrow therapeutic index drugs. J of Thrombosis and Thromblysis. 1999;7:137-143.
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31. EMA/618604/2008 Rev. July 2010, EWP of the CHMP.
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34. Buclin T, Thoma Y, Widmer N, et al. The steps to therapeutic drug monitoring: a structured approach illustrated with imatinib. Front. Pharmacol. 2020.
35. Garzon V, Bustos RH, Pinacho DG. Personalized medicine for antobiotics: the role of nanobiosensors in therapeutic drug monitoring. J Pers Med. 2020;10(4):147-181.
36. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009 Mar,24(1):1-10.
37. Johnston A. Equivalence and interchangeability of narrow therapeutic index in organ transplantation. Eur J Hosp Pharm. 2013;20:302-307.
38. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologists. CJASN. 2007;2(2):374-384.
39. Colombo D, Egan CG. Bioavailability of Sandimmun versus Sandimmun Neoral: a meta-analysis of published studies. Int J Immunopathol Pharmacol. 2010;23(4):1177-1183.
40. Taber DJ, Baillie GM, Ashcraft EE, et al. Does bioequivalence between modified cyclosporine formulations translate into equal outcomes? Transplantation. 2005;80:1633-1635.
41. Pollard S, Nashan B, Johnston A, et al. A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Berlin, Germany, Nov 19, 2003;25:1654-1669.
42. Kahan BD, Welsh M, Urbauer DL, et al. Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care cost. J Am Soc Nephrol. 2000;11:1122-1131.
43. Thongprayoon C, Hansrivijit P, Kovvuru K, et al. Impacts of high intra- and inter-individual variability in tacrolimus pharmacokinetics and fast tacrolimus metabolism on outcomes of solid organ transplantation recipients. J Clin Med. 2020;9:2192-2204.
44. Kuypers, D.R.J. Intrapatient variability of Tacrolimus exposure in solid organ transplantation: a novel marker for clinical outcome. Clin. Pharmacol. Ther. 2020;107:347–358.
45. Kaya Aksoy G, Comak E, Koyun M, et al. Tacrolimus variability: a cause of donor-specific anti-HLA antibody formation in children. Eur J Drug Metab Pharmacokinet. 2019;44:539–548.
46. Shuker N, Shuker L, van Rosmalen J, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation. Transpl Int. 2016;29:1158–1167.
47. Gatault P, Kamar N, Büchler M, et al. Reduction of extended-release Tacrolimus dose in low-immunological-risk kidney transplant recipients increases risk of rejection and appearance of donor-specific antibodies: a randomized study. Am J Transplant. 2017;17:1370–1379.
48. Van Gelder T. Commentary on the recommendations of the European Society for organ transplantation advisory committee on generic substitution of immunosuppressive drugs. GaBI J. 2013;2(3):108-109.
2. Sayegh MH, Carpenter CB. Transplantation 50 years later-progress, challenges, and promises. N Eng J Med. 2004; 351(26):2761-2766.
3. https://www.ctstransplant.org home page
4. Heldal K, Hartmann A, Grootendorst DC, et al. Benefit of kidney transplantation beyond 70 years of age. Nephro Dial Transplant. 2010;25:1680-1687.
5. Katznelson S, Cecka M. Immunosuppressive regimens and their effects on renal allograft outcome. Clin Transpl. 01 Jan 1996;361-371.
6. Enderby C, Keller C. An Overview of immunosuppression in solid organ transplantation. Am J Manag Care. 2015;21:S12-S23.
7. NICE 2019. https://www.nice.org.uk/guidance/ta481/resources/immunosuppressive-therrapy-for-kidney-transplant-in-adult-pdf
8. Scientific registry of transplant recipients website. https://www.srtr.org/annual_Reports/2011/109b_dh.aspx
9. Villard J. Immunity after organ transplantation. Swiss Med Wkly. 2006;136:71-77.
10. Deathridge J. Transplant immunology. British Society for Immunology Sep 2017.
11. Mourik IDM, Thomson M, Kelly D. Comparison of pharmacokinetics of neoral and Sandimmune in stable pediatric liver transplant recipients. Liver Transplantation and Surgery. 1999;5(2):107-111.
12. Saeki T, Ueda K, Tanigawara Y, et al. Human P-glycoprotein transports cyclosporine A and FK506. J Biol Chem. 1993;268:6077-6080.
13. Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27:383–391.
14. MacPhee IA, Fredericks S, Tai T, et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant. 2004;4:914-919.
15. MacPhee IA, Fredericks S, Mohamed M, et al. Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation. 2005;79:499-502.
16. Thervet E, Anglicheau D, King B, et al. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation. 2003;76:1233-1235.
17. Ameyaw MM, Regateiro F, Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics. 2001;11:217–221.
18. Mai I, Stömer E, Goldammer M, et al. MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol. 2003;43:1101–1107.
19. Zhang X, Liu Z, Zheng J, et al. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin Transplant. 2005;19:638-643.
20. Haufroid V, Mourad M, van Kerckove V, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14:147-154.
21. Sandimmune (cyclosporine) [package insert]. East Hanover, NJ:Novartis Pharmaceuticals; 2005.
22. Prograf (tacrolimus) [package insert]. Deerfield, IL: Astellas Pharma US; 2006.
23. Webster A, Woodroffe RD, Taylor RS, et al. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients (Cochrane Review). In: The Cochrane Library, Issue 2, 2006. Chichester: Wiley.
24. Srinivas TR, Stephany BR, Budev M, et al. An emerging population: kidney transplant candidates who are placed on the waiting list after liver, heart, and lung transplantation. Clin J Am Soc Nephrol. 2010;5(10):1881-1886. Epub 2010 Sep 2.
25. Sommerer C, Giese T, Meuer S, et al. Pharmacodynamic monitoring of calcineurin inhibitor therapy: Is there a clinical benefit? NDT. Jan 2009;24(1):21-27.
26. Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nature Reviews. Drug Discovery. October 2012;11(10):751–61. DOI 10.1038/nrd3801. PMID 22935759.
27. Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015;71:549-567. DOI 10.1007/s00228-015-1832-0.
28. Tariq Ahmad. Pharmacological classification of drugs. 1st ed. Dept. of Pharmacy, Univ of Lahore.
29. Maureen Burns. Management of narrow therapeutic index drugs. J of Thrombosis and Thromblysis. 1999;7:137-143.
30. Baumgartel C, Godman B. Bioequivalence of narrow therapeutic index drugs and immunosuppressives. Generics and Biosimilars Initiative J. 2015;4(4):159-160.
31. EMA/618604/2008 Rev. July 2010, EWP of the CHMP.
32. Ghiculescu, R. Therapeutic drug monitoring: Which drugs, why, when and how to do it. Aust. Prescr. 2008;31:42–44.
33. Figueras A. Review of the evidence to include TDM in the essential in vitro diagnostics list and prioritization of medicines to be monitored. WHO: Geneva, Switzerland, Feb 18th, 2019.
34. Buclin T, Thoma Y, Widmer N, et al. The steps to therapeutic drug monitoring: a structured approach illustrated with imatinib. Front. Pharmacol. 2020.
35. Garzon V, Bustos RH, Pinacho DG. Personalized medicine for antobiotics: the role of nanobiosensors in therapeutic drug monitoring. J Pers Med. 2020;10(4):147-181.
36. Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med. 2009 Mar,24(1):1-10.
37. Johnston A. Equivalence and interchangeability of narrow therapeutic index in organ transplantation. Eur J Hosp Pharm. 2013;20:302-307.
38. Schiff J, Cole E, Cantarovich M. Therapeutic monitoring of calcineurin inhibitors for the nephrologists. CJASN. 2007;2(2):374-384.
39. Colombo D, Egan CG. Bioavailability of Sandimmun versus Sandimmun Neoral: a meta-analysis of published studies. Int J Immunopathol Pharmacol. 2010;23(4):1177-1183.
40. Taber DJ, Baillie GM, Ashcraft EE, et al. Does bioequivalence between modified cyclosporine formulations translate into equal outcomes? Transplantation. 2005;80:1633-1635.
41. Pollard S, Nashan B, Johnston A, et al. A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Berlin, Germany, Nov 19, 2003;25:1654-1669.
42. Kahan BD, Welsh M, Urbauer DL, et al. Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care cost. J Am Soc Nephrol. 2000;11:1122-1131.
43. Thongprayoon C, Hansrivijit P, Kovvuru K, et al. Impacts of high intra- and inter-individual variability in tacrolimus pharmacokinetics and fast tacrolimus metabolism on outcomes of solid organ transplantation recipients. J Clin Med. 2020;9:2192-2204.
44. Kuypers, D.R.J. Intrapatient variability of Tacrolimus exposure in solid organ transplantation: a novel marker for clinical outcome. Clin. Pharmacol. Ther. 2020;107:347–358.
45. Kaya Aksoy G, Comak E, Koyun M, et al. Tacrolimus variability: a cause of donor-specific anti-HLA antibody formation in children. Eur J Drug Metab Pharmacokinet. 2019;44:539–548.
46. Shuker N, Shuker L, van Rosmalen J, et al. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation. Transpl Int. 2016;29:1158–1167.
47. Gatault P, Kamar N, Büchler M, et al. Reduction of extended-release Tacrolimus dose in low-immunological-risk kidney transplant recipients increases risk of rejection and appearance of donor-specific antibodies: a randomized study. Am J Transplant. 2017;17:1370–1379.
48. Van Gelder T. Commentary on the recommendations of the European Society for organ transplantation advisory committee on generic substitution of immunosuppressive drugs. GaBI J. 2013;2(3):108-109.