Clinical Pharmacokinetic Monitoring of Leflunomide in Renal Transplant Recipients with BK Virus Reactivation: A Review of the Literature

Clinical Pharmacokinetics

Volumn 56, Issue 9, 2017, Pages 1015-1031

  Ng, Joan C Y ^a,b   Leung, Marianna ^a,b   Wright, Alissa J ^a   Ensom, Mary H H ^a,c  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b Providence Health Care   (Canada)

^c CHILDREN S AND WOMEN S HEALTH CENTRE OF BRITISH COLUMBIA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

LEFLUNOMIDE; ISOXAZOLE DERIVATIVE;

BK VIRUS; CLINICAL DECISION MAKING; DRUG CLEARANCE; DRUG DETERMINATION; DRUG ELIMINATION; DRUG INTERACTION; DRUG MONITORING; GENETIC POLYMORPHISM; GRAFT RECIPIENT; HUMAN; KIDNEY DISEASE; KIDNEY TRANSPLANTATION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT DURATION; TREATMENT INDICATION; TREATMENT RESPONSE; VIREMIA; VIRUS REACTIVATION; ANIMAL; BLOOD; DRUG EFFECT; PHYSIOLOGY; POLYOMAVIRUS INFECTION; PROCEDURES; PROSPECTIVE STUDY; RETROSPECTIVE STUDY; TRENDS; VIRUS ACTIVATION; VIRUS INFECTION;

ANIMALS; BK VIRUS; CLINICAL DECISION-MAKING; HUMANS; ISOXAZOLES; KIDNEY TRANSPLANTATION; POLYOMAVIRUS INFECTIONS; PROSPECTIVE STUDIES; RETROSPECTIVE STUDIES; TRANSPLANT RECIPIENTS; TUMOR VIRUS INFECTIONS; VIRUS ACTIVATION;

EID: 85014050972     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.1007/s40262-017-0521-9     Document Type: Review

References (65)

1. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1–155.
2. (CIHI) CI for HI. 2015 CORR report: treatment of end-stage organ failure in Canada, 2004 to 2013. 2015. https://secure.cihi.ca/estore/productFamily.htm?locale=en&pf=PFC2864&lang=en. Accessed 17 Nov 2016.
3. Womer KL, Kaplan B. Recent developments in kidney transplantation—a critical assessment. Am J Transplant. 2009;9(6):1265–71.
4. Yabu JM, Vincenti F. Kidney Transplantation: the ideal immunosuppression regimen. Adv Chronic Kidney Dis. 2009;16(4):226–33.
5. Dharnidharka VR, Abdulnour HA, Araya CE. The BK virus in renal transplant recipients—review of pathogenesis, diagnosis, and treatment. Pediatr Nephrol. 2010;26(10):1763–74.
6. Balba GP, Javaid B, Timpone JG Jr. BK polyomavirus infection in the renal transplant recipient. Infect Dis Clin N Am. 2013;27(2):271–83.
7. Bazin C. Leflunomide an immunosuppressive drug for antiviral purpose in treatment for BK virus-associated nephropathy after kidney transplantation. In: Arbuthnot P, editor. Antiviral drugs—aspects of clinical use and recent advances. InTech; 2012. http://www.intechopen.com/books/antiviral-drugs-aspects-of-clinical-use-and-recent-advances/leflunomide-an-immunosuppressive-drug-for-antiviral-purpose-in-treatment-for-bk-virus-nephropathy-af. Accessed 27 Jan 2016.
8. Saad ER, Bresnahan BA, Cohen EP, Lu N, Orentas RJ, Vasudev B, et al. Successful treatment of BK viremia using reduction in immunosuppression without antiviral therapy. Transplantation. 2008;85(6):850–4.
9. Vasudev B, Hariharan S, Hussain SA, Zhu Y-R, Bresnahan BA, Cohen EP. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005;68(4):1834–9.
10. Funk GA, Steiger J, Hirsch HH. Rapid dynamics of polyomavirus type BK in renal transplant recipients. J Infect Dis. 2006;193(1):80–7.
11. Ensom MHH, Davis GA, Cropp CD, Ensom RJ. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes? Clin Pharmacokinet. 1998;34(4):265–79.
12. Rozman DB. Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet. 2012;41(6):421–30.
13. Oh J, O’Connor PW. Teriflunomide in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2014;7(5):239–52.
14. Kalgutkar AS, Nguyen HT, Vaz ADN, Doan A, Dalvie DK, McLeod DG, et al. In vitro metabolism studies on the isoxazole ring scission in the anti-inflammatory agent lefluonomide to its active alpha-cyanoenol metabolite A771726: mechanistic similarities with the cytochrome P450-catalyzed dehydration of aldoximes. Drug Metab Dispos. 2003;31(10):1240–50.
15. Center for Drug Evaluation and Research. Drug approval package: Aubagio (Teriflunomide) tablets. Clinical Pharmacology and Biopharmaceutics Review(s): NDA992; 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000SumR.pdf. Accessed 18 Feb 2017.
16. Hopkins A, Wiese M, Proudman S, O’Doherty C, Foster D, Upton R. Semiphysiologically based pharmacokinetic model of leflunomide disposition in rheumatoid arthritis patients. CPT Pharmacomet Syst Pharmacol. 2015;4(6):362–71.
17. Bergner R, Peters L, Schmitt V, Löffler C. Leflunomide in dialysis patients with rheumatoid arthritis—a pharmacokinetic study. Clin Rheumatol. 2012;32(2):267–70.
18. Arava® (leflunomide): product monograph. Laval: Sanofi-Aventis; 2015. p. 1–70. http://products.sanofi.ca/en/arava.pdf. Accessed 18 Feb 2017.
19. Kim K-A, Joo H-J, Park J-Y. Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level. Eur J Clin Pharmacol. 2010;67(2):129–34.
20. Chong A, Zeng H, Knight D, Shen J, Meister G, Williams J, et al. Concurrent antiviral and immunosuppressive activities of leflunomide in vivo. Am J Transplant. 2006;6(1):69–75.
21. Knight DA, Hejmanowski AQ, Dierksheide JE, Williams JW, Chong AS, Waldman WJ. Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide. Transplantation. 2001;71(1):170–4.
22. Schläpfer E, Fischer M, Ott P, Speck RF. Anti-HIV-1 activity of leflunomide: a comparison with mycophenolic acid and hydroxyurea. AIDS. 2003;17(11):1613–20.
23. Liacini A, Seamone ME, Muruve DA, Tibbles LA. Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation. 2010;90(12):1450–7.
24. Bernhoff E, Tylden GD, Kjerpeseth LJ, Gutteberg TJ, Hirsch HH, Rinaldo CH. Leflunomide inhibition of BK virus replication in renal tubular epithelial cells. J Virol. 2010;84(4):2150–6.
25. Josephson MA, Gillen D, Javaid B, Kadambi P, Meehan S, Foster P, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006;81(5):704–10.
26. Krisl JC, Taber DJ, Pilch N, Chavin K, Bratton C, Thomas B, et al. Leflunomide efficacy and pharmacodynamics for the treatment of BK viral infection. Clin J Am Soc Nephrol. 2012;7(6):1003–9.
27. Johnston O, Jaswal D, Gill JS, Doucette S, Fergusson DA, Knoll GA. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. 2010;89(9):1057–70.
28. Leca N, Muczynski KA, Jefferson JA, de Boer IH, Kowalewska J, Kendrick EA, et al. Higher levels of leflunomide are associated with hemolysis and are not superior to lower levels for BK virus clearance in renal transplant patients. Clin J Am Soc Nephrol. 2008;3(3):829–35.
29. ®). Lexi-Comp, Inc.; 2016. https://online.lexi.com/. Accessed 18 Feb 2017.
30. Vancouver Acute Pharmaceutical Sciences. Special access program & non-formulary drugs. List of monographs. http://www.vhpharmsci.com/PDTM/pdtm-SAP-&-NF-index.htm. Accessed 16 Feb 2016.
31. Drugs@FDA: FDA approved drug products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=Cidofovir&SearchType=BasicSearch. Accessed 18 Nov 2016.
32. Sener A, House AA, Jevnikar AM, Boudville N, McAlister VC, Muirhead N, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one-year follow-up of renal allograft recipients. Transplantation. 2006;81(1):117–20.
33. Wittstock M, Benecke R, Zettl UK. Therapy with intravenous immunoglobulins: complications and side-effects. Eur Neurol. 2003;50(3):172–5.
34. Knoll GA, Humar A, Fergusson D, Johnston O, House AA, Kim SJ, et al. Levofloxacin for BK virus prophylaxis following kidney transplantation: a randomized clinical trial. JAMA. 2014;312(20):2106–14.
35. Zeidan S, Esposito L, Rostaing L, Kamar N. The Achilles tendon of preventing BK virus nephropathy. Transpl Infect Dis. 2013;15(6):E268–9.
36. Chan V, Charles BG, Tett SE. Rapid determination of the active leflunomide metabolite A77 1726 in human plasma by high-performance liquid chromatography. J Chromatogr B. 2004;803(2):331–5.
37. Dias VC, Lucien J, LeGatt DF, Yatscoff RW. Measurement of the active leflunomide metabolite (A77 1726) by reverse-phase high-performance liquid chromatography. Ther Drug Monit. 1995;17(1):84–8.
38. Parekh JM, Vaghela RN, Sutariya DK, Sanyal M, Yadav M, Shrivastav PS. Chromatographic separation and sensitive determination of teriflunomide, an active metabolite of leflunomide in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B. 2010;878(24):2217–25.
39. Rakhila H, Rozek T, Hopkins A, Proudman S, Cleland L, James M, et al. Quantitation of total and free teriflunomide (A77 1726) in human plasma by LC–MS/MS. J Pharm Biomed Anal. 2011;55(2):325–31.
40. Schmidt A, Schwind B, Gillich M, Brune K, Hinz B. Simultaneous determination of leflunomide and its active metabolite, A77 1726, in human plasma by high-performance liquid chromatography. Biomed Chromatogr. 2003;17(4):276–81.
41. Sobhani K, Garrett DA, Liu D-P, Rainey PM. A rapid and simple high-performance liquid chromatography assay for the leflunomide metabolite, teriflunomide (A77 1726), in renal transplant recipients. Am J Clin Pathol. 2010;133(3):454–7.
42. van Roon EN, Yska JP, Raemaekers J, Jansen TLTA, van Wanrooy M, Brouwers JRBJ. A rapid and simple determination of A77 1726 in human serum by high-performance liquid chromatography and its application for optimization of leflunomide therapy. J Pharm Biomed Anal. 2004;36(1):17–22.
43. Hüttemann M, Shipkova M, Klett C, Hasche G, Wilhelm J, Bolley R, et al. Total and free plasma concentrations of the active metabolite of leflunomide in relation to therapeutic outcome in kidney transplant recipients with BK virus nephropathy. Transplant Proc. 2013;45(4):1611–3.
44. Williams JW, Javaid B, Kadambi PV, Gillen D, Harland R, Thistlewaite JR, et al. Leflunomide for polyomavirus type BK nephropathy. N Engl J Med. 2005;352(11):1157–8.
45. Chan V, Charles BG, Tett SE. Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis. Br J Clin Pharmacol. 2005;60(3):257–64.
46. Li EK, Tam L-S, Tomlinson B. Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004;26(4):447–59.
47. Miller AE. Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis. Clin Ther. 2015;37(10):2366–80.
48. van Roon EN, Jansen TLTA, van de Laar MAFJ, Janssen M, Yska JP, Keuper R, et al. Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2005;64(4):569–74.
49. Faguer S, Hirsch HH, Kamar N, Guilbeau-Frugier C, Ribes D, Guitard J, et al. Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation. Transpl Int. 2007;20(11):962–9.
50. Teschner S, Gerke P, Geyer M, Wilpert J, Krumme B, Benzing T, et al. Leflunomide therapy for polyomavirus-induced allograft nephropathy: efficient BK virus elimination without increased risk of rejection. Transplant Proc. 2009;41(6):2533–8.
51. Araya CE, Garin EH, Neiberger RE, Dharnidharka VR. Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients. Pediatr Transplant. 2010;14(1):145–50.
52. Bechert CJ, Schnadig VJ, Payne DA, Dong J. Monitoring of BK viral load in renal allograft recipients by real-time PCR assays. Am J Clin Pathol. 2010;133(2):242–50.
53. Cuellar-Rodriguez J, Stephany B, Poggio E, Mossad SB, Goldfarb D, Lard M, et al. Contrasting patterns of viral load response in transplant recipients with BK polyomavirus DNAemia on leflunomide therapy. Clin Transplant. 2013;27(3):E230–6.
54. Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J Am Soc Nephrol. 2008;3(Supplement 2):S68–75.
55. Drachenberg CB, Papadimitriou JC, Hirsch HH, Wali R, Crowder C, Nogueira J, et al. Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transplant. 2004;4(12):2082–92.
56. Beaman JM, Hackett LP, Luxton G, Illett KF. Effect of hemodialysis on leflunomide plasma concentrations. Ann Pharmacother. 2002;36(1):75–7.
57. Russo PA, Wiese MD, Smith MD, Ahern MJ, Barbara JA, Shanahan EM. Leflunomide for inflammatory arthritis in end-stage renal disease on peritoneal dialysis: a pharmacokinetic and pharmacogenetic study. Ann Pharmacother. 2013;47(3):e15.
58. Hirsch HH, Randhawa P, AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant. 2013;13(s4):179–88.
59. Waldman WJ, Knight DA, Blinder L, Shen J, Lurain NS, Miller DM, et al. Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide. Intervirology. 1999;42(5–6):412–8.
60. Waldman WJ, Knight DA, Lurain NS, Miller DM, Sedmak DD, Williams JW, et al. Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation. 1999;68(6):814–25.
61. Bohanec Grabar P, Grabnar I, Rozman B, Logar D, Tomšič M, Šuput D, et al. Investigation of the influence of CYP1A2 and CYP2C19 genetic polymorphism on 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide (A77 1726) pharmacokinetics in leflunomide-treated patients with rheumatoid arthritis. Drug Metab Dispos. 2009;37(10):2061–8.
62. FDA Center for Drug Evaluation and Research. Sanofi-Aventis. Clinical pharmacology and biopharmaceutics review: teriflunomide. 2001. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202992Orig1s000ClinpharmR.pdf. Accessed 18 Feb 2017.
63. Bohanec Grabar P, Rozman B, Tomsic M, Suput D, Logar D, Dolzan V. Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Eur J Clin Pharmacol. 2008;64(9):871–6.
64. Filali-Ansary A, Lunven C, Turpault S, Beyer Y-J, O’Brien A, Delfolie A, et al. Dried blood spot methodology in combination with liquid chromatography/tandem mass spectrometry facilitates the monitoring of teriflunomide. Ther Drug Monit. 2016;38(4):471–82.
65. Suneetha A, Raja RK. Comparison of LC-UV and LC–MS methods for simultaneous determination of teriflunomide, dimethyl fumarate and fampridine in human plasma: application to rat pharmacokinetic study. Biomed Chromatogr. 2016;30(9):1371–7.