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   Abstract
  Introduction
  Case Report
  Discussion
  Conclusion
  Acknowledgment
   References
   Article Figures

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  Table of Contents  
CASE REPORT
Year : 2013  |  Volume : 23  |  Issue : 1  |  Page : 71-73
 

Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients


1 Department of Pharmacology, Clinical Pharmacology Unit, Vellore, India
2 Department of Nephrology, Christian Medical College, Vellore, India

Date of Web Publication16-Feb-2013

Correspondence Address:
B S Mathew
Clinical Pharmacology Unit, Christian Medical College Hospital, Vellore, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-4065.107216

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  Abstract 

In patients undergoing renal transplantation, dose individualization for tacrolimus is routinely achieved with therapeutic drug monitoring (TDM). The patient started on 5.5 mg/day of tacrolimus had a significantly elevated tacrolimus trough concentration. The tacrolimus dose was regularly reduced following TDM at many time periods in the post transplant period but the tacrolimus concentration was consistently elevated. Genomic analysis done after four years revealed mutations in the genes encoding for CYP3A5 and MDR1 (2677G > T). Pharmacogenomics alongside TDM, will soon emerge as the backbone of dose individualization. But for genomics to be beneficial, it should be advocated in the pre-transplant or early post transplant period.


Keywords: Drug monitoring, polymorphism, tacrolimus


How to cite this article:
Manvizhi S, Mathew B S, Fleming D H, Basu G, John G T. Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients. Indian J Nephrol 2013;23:71-3

How to cite this URL:
Manvizhi S, Mathew B S, Fleming D H, Basu G, John G T. Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients. Indian J Nephrol [serial online] 2013 [cited 2019 Jul 18];23:71-3. Available from: http://www.indianjnephrol.org/text.asp?2013/23/1/71/107216



  Introduction Top


Tacrolimus-based regimen that includes induction with daclizumab and maintenance with mycophenolate mofetil and corticosteroids has superior efficacy in renal transplantation when compared with cyclosporine-based regimens. [1],[2] Pharmacodynamic and pharmacokinetic variability with tacrolimus have been attributed to various factors such as co-medication, biochemical, hematological parameters, and genetic constitution. [3],[4] Dose individualization for tacrolimus is routinely achieved with therapeutic drug monitoring. Recent literature highlights personalizing drug therapy using the pharmacogenomic approach. [5]

Inter-individual variability of tacrolimus is attributed to polymorphisms of Cyp3A5 and transporters as P glycoprotein. [6],[7] The presence of Cyp3A5*3 allele, CYP3A5*6, or MDR-1 (T-1236C, C3435T, and G2677T) are associated with an increased exposure to tacrolimus. Scholten et al. reported that tacrolimus area under the concentration time curve (AUC 0-12 ) of 210 ng.h/mL for 6 weeks post-transplant and 125 ng.h/mL thereafter would be adequate to prevent acute rejections. [8] For mycophenolate, the dosing is based on maintaining AUC 0-12 within 30-60 mg.h/L. [9]


  Case Report Top


A 50-year-old lady of mongoloid extraction from Bhutan, with chronic kidney disease resulting from membranous proliferative glomerulonephritis pre-emptively received a renal allograft from her haplo-matched cousin sister. Her pre-transplant donor-recipient crossmatch and donor-specific antibodies were negative. She received standard immunosuppressive therapy with mycophenolate sodium (1440 mg/day), tacrolimus (5.5 mg/day), and steroid (20 mg/day) with basiliximab induction. She was also prescribed valganciclovir, cotrimoxazole, pantoprazole, and calcium. During the first 2 months post-transplant the MPA AUC 0-12 ranged from 29.2 to 168.7 mg.h/L with total daily doses varying from 1440 to 1620 mg. She developed leukopenia which did not remit with reduction in dose of mycophenolate. Due to persistent leucopenia, other drugs such as valganciclovir and co-trimoxazole were stopped. Mycophenolate dose was gradually tapered but leucopenia continued to worsen therefore mycophenolate was stopped. Subsequently, leucocyte counts never increased more than 5000/cu.mm so mycophenolate could not be restarted. Renal and liver function parameters were within normal limits in the post-transplant period. The tacrolimus trough measurements (ng/ml) and the subsequent dose adjustments over time are shown in [Figure 1].
Figure 1: Tacrolimus dose (mg/kg) and trough measurements (ng/mL) over time

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Dose reductions for tacrolimus were made gradually over a 1½ month period. However, the trough concentration remained above the recommended trough concentration. Tacrolimus 2 point LSS AUC within the first post-transplant year ranged between 165.6 and 140.9 μg.h/L while on 2 mg/day in two divided doses, which was within the range of exposure in the maintenance period at this center. [10] Post-transplant immune monitoring with donor-specific antibody was negative throughout her follow-up. BK virus PCR screening remained negative when tested during serial visits.

Two years later, the two-point LSS tacrolimus AUC increased to 281.7 μg.h/L after initiation of ciprofloxacin which reduced to 217.3 μg.h/L, 1 week after discontinuation of ciprofloxacin.

In view of the possibility of polymorphism affecting tacrolimus metabolism, with informed consent, single nucleotide polymorphisms that could account for the elevated tacrolimus levels were tested for with PCR. She was mutant homozygous for CYP3A5*3(GG) alleles and MDR1-2677(TT) alleles, heterozygous for MDR1-1236(CT) alleles and wild-type homozygous for CYP3A5*6 (GG) and MDR1 3435C (CC) alleles.


  Discussion Top


The optimum therapeutic range of tacrolimus trough concentrations in our transplant unit for the immunosuppressive regimen with MPA, tacrolimus, and steroid is 5-10 ng/mL for the 1 st month after transplantation and 3-5 ng/mL thereafter, provided there is no evidence of rejection. Unlike other transplant patients, this patient was maintained on an immunosuppressive regimen of only tacrolimus and prednisolone, but at significantly higher tacrolimus trough concentrations than normal after stabilization (7-20 ng/mL). There were no clinical features of side effects including tremor or biochemical features of rejection or toxicity.

Mutations in the genes encoding for CYP3A5 and MDR 1 (2677G > T) explains the increased exposure to tacrolimus. The availability of this information in the early treatment period could have decreased the number of TDM specimens and if in future patients with this genotype can be managed on low doses of tacrolimus alone it will significantly reduce the cost of treatment. TDM is the proven cornerstone of dose individualization but pharmacogenomics has a vital role to play. In South Indians the frequency of CYP3A5*3 was found to be 63.5% which is significantly different from the incidence among the African Americans, Caucasians (87.3%), and Chinese population. [11]


  Conclusion Top


This case report gives rise to a number of questions. Can other patients with this genotype be maintained on only low dose tacrolimus with steroids? Will a mandatory genetic screening of patients undergoing renal transplant reduce the overall cost and time to individualized therapy? Would it be necessary to define a different tacrolimus trough therapeutic range for patients maintained on only two drug immunosuppressive regimen (tacrolimus + steroid).


  Acknowledgment Top


We would like to sincerely thank Dr. Poonkuzhali Balasubramanian and Savitha Varadarajan, Department of Hematology, Christian Medical College Hospital, Vellore for their help with pharmacogenomic analysis.

 
  References Top

1.Guerra G, Ciancio G, Gaynor JJ, Zarak A, Brown R, Hanson L, et al. Randomized trial of immunosuppressive regimens in renal transplantation. J Am Soc Nephrol 2011;22:1758-68.  Back to cited text no. 1
[PUBMED]    
2.Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gürkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562-75.  Back to cited text no. 2
    
3.Press RR, Ploeger BA, den Hartigh J, van der Straaten T, van Pelt J, Danhof M, et al. Explaining variability in tacrolimus pharmacokinetics to optimize early exposure in adult kidney transplant recipients. Ther Drug Monit 2009;31:187-97.  Back to cited text no. 3
[PUBMED]    
4.Armendáriz Y, García S, Lopez RM, Pou L. Hematocrit influences immunoassay performance for the measurement of tacrolimus in whole blood. Ther Drug Monit 2005;27:766-9.  Back to cited text no. 4
    
5.Thervet E, Loriot MA, Barbier S, Buchler M, Ficheux M, Choukroun G, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther 2010;87:721-6.  Back to cited text no. 5
    
6.Haufroid V, Wallemacq P, VanKerckhove V, Elens L, De Meyer M, Eddour DC, et al. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: Guidelines from an experimental study. Am J Transplant 2006;6:2706-13.  Back to cited text no. 6
    
7.Hawwa AF, McKiernan PJ, Shields M, Millership JS, Collier PS, McElnay JC. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol 2009;68:413-21.  Back to cited text no. 7
    
8.Scholten EM, Cremers SC, Schoemaker RC, Rowshani AT, van Kan EJ, den Hartigh J, et al. AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney Int 2005;67:2440-7.  Back to cited text no. 8
    
9.van Gelder T, Le Meur Y, Shaw LM, Oellerich M, DeNofrio D, Holt C, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit 2006;28:145-54.  Back to cited text no. 9
    
10.Mathew BS, Fleming DH, Jeyaseelan V, Chandy SJ, Annapandian VM, Subbanna PK, et al. A limited sampling strategy for tacrolimus in renal transplant patients. Br J Clin Pharmacol 2008;66:467-72.  Back to cited text no. 10
    
11.Krishnakumar D, Gurusamy U, Dhandapani K, Surendiran A, Baghel R, Kukreti R, et al. Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Fundam Clin Pharmacol 2012;26:295-306.  Back to cited text no. 11
    


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