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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 14  |  Issue : 1  |  Page : 8-14

Therapeutic drug monitoring of tacrolimus in kidney transplantation


Department of Nephrology and Kidney Transplantation, Medanta Kidney and Urology Institute, Medanta Medicity, Gurgaon, Haryana, India

Date of Submission19-Jan-2020
Date of Acceptance24-Feb-2020
Date of Web Publication31-Mar-2020

Correspondence Address:
Dr. Shyam Bihari Bansal
Medanta Kidney and Urology Institute, Medanta Medicity, Sector 38, Gurgaon - 122 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_4_20

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  Abstract 


Calcineurin inhibitors (CNI) are the backbone of present-day immunosuppressive regimen in kidney transplant recipients. Tacrolimus (TAC) has gradually replaced cyclosporine as CNI of choice due to its better potency and side effect profile. One of the key challenges in using TAC is therapeutic drug monitoring (TDM) of TAC, as it is a drug of narrow therapeutic index. Various methods of TDM are available; there are older immunoassay (IA)-based methods and recent liquid chromatogram (LC) based. The problems with older IAs like microparticle enzyme IA (Abbott Diagnostics, Chicago, IL, USA), and enzyme multiplied IA (EMIT, Dade Behring, Glasgow, DE, USA) are; they are not so accurate, there is interference with other substances, they measure inactive metabolite, and their limit of detection is not wide. The LC-based methods such as liquid chromatogram mass spectroscopy or LC-tandem mass spectroscopy overcome these issues; however, they are costly, labor intensive, and require good technical support. Newer IAs, such as chemiluminescent microparticle IA (Abbott Diagnostics) and Quantitative Microsphere System (QMS™, Thermo-Fisher), have functional sensitivity <1 ng/ml, and overcome the disadvantages of older IAs. These newer IA are reported to offer adequate accuracy and precision, and at the same time, they are easy to perform. There is genetic variation in expression of cytochrome p-450 (CYP3A4) and CYP3A5 enzymes, which metabolizes TAC, resulting in different levels with same doses. Patients who are expressers (CYP3A5 1*/1* OR CYP3A5 1*/3*) require higher doses to maintain the same levels compared to nonexpressers (CYP3A5 3*/3*).

Keywords: Drug monitoring, kidney transplant, tacrolimus


How to cite this article:
Bansal SB. Therapeutic drug monitoring of tacrolimus in kidney transplantation. Indian J Transplant 2020;14:8-14

How to cite this URL:
Bansal SB. Therapeutic drug monitoring of tacrolimus in kidney transplantation. Indian J Transplant [serial online] 2020 [cited 2020 Jul 6];14:8-14. Available from: http://www.ijtonline.in/text.asp?2020/14/1/8/281763




  Introduction Top


Kidney transplantation is considered the best treatment modality for patients with kidney failure. Transplant recipients require lifelong immunosuppression. Nowadays, most centers use triple immunosuppression, consisting of calcineurin inhibitor (CNI) (tacrolimus [TAC] or cyclosporine), an antimetabolite (mycophenolate mofetil [MMF] or azathioprine), and corticosteroids. The CNIs form the backbone of present-day immunosuppressive regimens and most centers worldwide have now shifted to TAC-based immunosuppression.[1] For better graft and patient survival, it is essential to optimize the degree of immunosuppression, as over-immunosuppression might lead to increase adverse effects and under-immunosuppression predisposes to rejection.[2],[3] To achieve this balance and to individualize drug dosing, therapeutic drug monitoring (TDM) of various immunosuppressive drugs is required.

TAC was introduced in 1994 by Fujisawa Healthcare (now Astellas) and initially was used in liver transplantation. TAC is a CNI like cyclosporine and prevents the activation of T cells; however, it is hundred times more potent than cyclosporine.[4] TAC is a drug with a narrow therapeutic window and TDM is necessary to keep the level within a therapeutic range to minimize the adverse effects and yet maintain levels inadequate range to prevent rejection.[5] TAC, in addition to various side effects, predispose to nephrotoxicity at higher levels. In addition, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of TAC are different between patients and within the same patient, exposing them to either underexposure or toxicity, and hence, it is extremely important to do TDM of TAC.[5],[6]


  the Pharmacokinetics and Pharmacodynamics Top


The oral bioavailability of TAC is about 25% (4%–89%), with peak steady-state concentration occurring within 1.5 h after dosing. The half-life of TAC is 12–15 h [Figure 1]. TAC is metabolized by cytochrome p-450 (CYP) 34A enzyme in intestine and hepatocyte, activities of which are different in different individuals.[6] In addition, levels are affected by intestinal absorption, as poor and unpredictable intestinal absorption might alter the levels. In hepatic dysfunction, TAC clearance might decrease up to 30%, leading to increase in TAC levels.[5],[6] Unlike cyclosporine, absorption of TAC is bile independent; thus, it does not interfere with enterohepatic cycling and does not decrease the MMF concentration. TAC is concentrated in red blood cells, that's why the TAC level is measured in whole blood rather than in plasma.[5],[6],[7]
Figure 1: Pharmacokinetics and pharmacodynamics of tacrolimus

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Factors affecting the therapeutic drug concentration and efficacy of TAC in transplant are: type of organ transplanted, age of the patient, time since transplant, method used for monitoring drug level, type of sampling (trough, limited sample strategy [LSS], or area under curve [AUC]), concomitant immunosuppression and race (African–Americans require higher doses of drugs as compared to Caucasians).[6]

The recently available once a day TAC formulation (advagraf) is absorbed in the distal gastrointestinal tract, and it has lower maximal concentration (C max) and longer time to achieve maximum concentration (T max) as compared to twice-daily formulation.[8]

The relationship between TAC whole blood trough level and efficacy and toxicity has been widely studied.[3],[9],[10],[11] In kidney transplantation, the relationship has been seen between increasing maximum trough concentration of TAC and toxicity within 7 days posttransplant and decreasing rates of acute rejection (AR) with increasing minimum trough concentration; however, similar strong relationship is not observed between low trough concentration and rejection.[9] One study found the correlation between the increase in rejection episode with low TAC AUC level on day 2 posttransplant, but the same was not seen at 2 weeks or 3 months.[3] In liver transplantation, a multicenter prospective study found significant co-relationship between maximum trough concentration and decreasing AR rates and increasing toxicity.[11] In addition, the nature of the adverse effect and drug concentration differs as neurotoxicity, nephrotoxicity, and hypertension seem to display a stronger relationship with blood levels than diarrhea or new-onset diabetes after transplant (NODAT).[12]

In 2009, a panel of European experts met at Brussels to discuss recent advances in the management of TAC monitoring according to the specific clinical situations, about the analytic method of monitoring currently in use and came up with some guidelines and recommendations.[13]


  Therapeutic Drug Monitoring Strategies Top


Several strategies of TDM of TAC are available. The best marker of drug exposure is area under the curve (AUC 0–12 h), in which multiple samples are taken at different time intervals.[14],[15] In day-to-day practice, it is expensive and not practical. Most centers use whole blood trough concentration (C0) for monitoring TAC exposure; however, this method is not as accurate and correlation with AUC is a matter of debate. A better correlation between trough level and AUC has been seen in the early phase of transplant than later.[9],[15] Moreover, there is a difference between morning and evening trough levels and trough level increases with the time of transplantation. The correlation between 2 h TAC level (C2) with AUC is not as good as with cyclosporine, and hence, it is not used for TDM.[16] In addition, there is significant inter-individual (20%–60%) and intra-individual (10%–40%) variability in trough levels of TAC. Once a day formulation of TAC has less intra-patient variability; however, the trough levels and AUC are slightly lower that twice-daily formulation.[8] The coefficient of determination (r2) varying between 0.11 and 0.93 in AUC and trough is seen, and there is a poor correlation of trough levels with clinical efficacy.[17] Some studies have found a better correlation with TAC, C3, or C4 with AUC C0–12 in solid organ transplantation.[18],[19] There are limited data to suggest the target AUC in this population. One study has suggested a range of >200 ng/ml/h to be highly discriminatory to prevent AR.[3]

Another strategy to monitor drug exposure is LSS, in which instead of using multiple samples, only 2 or 3 samples are taken. Scholten et al. established a population-based pharmacokinetic model for TAC and developed a Bayesian estimator based on an LSS of 2 points (C0 plus any other single point between C2 and C4) and then, they performed an AUC-guided dosing study in 15 renal transplant recipients. They demonstrated good clinical results and suggested AUC target between 150 and 200 ng/mL/h as the appropriate level.[15] Further prospective studies analyzing the interest in TAC AUC-based TDM are required.

Good correlation has been seen in one study between AUC 0–12 h and LSS; however, this needs validation in larger multicentre studies.[17]


  Target Trough Levels for Tacrolimus Top


When TAC was first introduced into clinical practice, the range of trough level was very broad, between 5 and 40 ng/ml; however later on, this was narrowed down to 10–20 ng/ml. In the first consensus conference on TAC in 1995, this range was further lowered between 5 and 20 ng/ml.[5] Later on, with the introduction of monoclonal antibodies (basiliximab and daclizumab) and MMF, the AR rates decreased to 8%–20% as compared to 40%–45% earlier.[20],[21] The target trough level of TAC with antibody induction and triple immunosuppression comprising MMF has been further reduced to 10–15 ng/ml or even 8–12 ng/ml.[21],[22],[23]

The Symphony study, which was a multicenter randomized controlled trial, compared low dose of TAC aiming target trough levels between 3 and 7 ng/ml with the standard dose, low dose cyclosporine, and reduced dose sirolimus along with MMF 2 g/day. The study found that low dose TAC with adequate dose MMF and antibody induction had the lowest rates of AR and best graft function (eGFR - 65 ml/min) at 12 months. Although the actual levels of TAC achieved were higher (8.0 ± 2.2 and 6.4 ± 1.2 ng/ml) at 3 months and 12 months, respectively.[21] There is the suggestion by recent consensus meeting in Brussels that TAC trough level can be kept between 5 and 10 ng/ml in 1st year, when used along with IL-2 RA, corticosteroids, and MMF. However, the suggested target ranges are not guidelines, but observation made in recent studies.[13] These target ranges are all done on immunoassays (IAs) and prospective studies are required for therapeutic ranges for liquid chromatography-mass spectroscopy (LCMS).

Even with these low trough levels, the incidence of diarrhea (27%) and NODAT (10%) was not low in the Symphony study.[21] A recent study has shown that patients whose TAC levels are maintained >5 have lower chances of developing AR as compared to those whose TAC levels are maintained below 4 at 12 months. Hence, it is better to keep TAC level between >5 in the maintenance phase.[24]

With the recent lowering of the TAC target concentration range, there has been improvement in adverse effects such as neurotoxicity, NODAT, and some improvement in nephrotoxicity. It is stated in recent consensus meeting, that the levels of TAC have reached to its optimum levels of efficacy and toxicity, where further improvement seems difficult with current immunosuppression.[13] [Table 1] shows the proposed targets for kidney transplant recipients.
Table 1: Proposed target tacrolimus co concentration (ng/ml) guidelines for kidney transplantation

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  Methods to Measure Tacrolimus Level Top


Several methods of measurement of the TAC level are available. As TAC is concentrated in red blood cells, so data on measurement of TAC levels are based on whole blood samples.

Two types of assays are used for TDM of TAC–IAs and liquid chromatogram (LC). The IAs are more commonly used. The various types of IAs are-enzyme linked immunosorbent assay (Diasorin, Stillwater, MN, USA), microparticle enzyme immunoassay (MEIA, Abbott Diagnostics, Chicago, IL, USA), radioimmunoassay, enzyme multiplied IA (EMIT, Dade Behring, Glasgow, DE, USA), antibody-conjugated magnetic IA (ACMIA, Dade Behring Siemens Deerfield, IL, USA), cloned enzyme donor IA (Microgenics, Fremont, CA, USA), chemiluminescence immunoassay (CMIA), and fluorescence polarization immunoassay.[25],[26],[27],[28],[29],[30],[31],[32],[33],[34]

There are certain advantages and disadvantages of using each of these methods. The IAs are easy to operate, cheap, and can be incorporated easily in the existing automated system without much technical support.[25],[26],[27],[28],[29] However, there are certain disadvantages of IA i.e., cross-reactivity with the metabolite of drugs, which leads to overestimation of drug levels, all drugs cannot be measured simultaneously, and they are also affected by endogenous substances such as albumin and hematocrit.[30],[31] There is a significant overestimation of TAC levels by older IAs (MEIA, EMIT) as compared to LCMS.[27] MEIA can overestimate TAC concentration by 10%–40% as compared to HPLC-MS if hematocrit is low and can be overestimated by 5%–50% in patients with low albumin (<3 g/dL), similarly in patients with high hematocrit, there is the underestimation of level by 0%–20% with MEIA.[30],[31] Newer IAs like CMIA and ACMIA, do not have these interferences and detect levels up to 2–4 ng/ml.[32],[33],[34] Only two available IAs-CMIA (Abbott Diagnostics) and Quantitative Microsphere System (QMS™, Thermo-Fisher) have a functional sensitivity <1 ng/ml, and were reported to offer adequate accuracy and precision.[32],[33] Current target ranges are based on IAs using MEIA and not on other IAs developed later.[13]

CMIA is developed for the Architect platform. The Architect IA by Abbott has the advantage of minimal cross-reactivity with metabolites. In the Abbott Architect platform, there is interference with metabolite M-II, but it is a biologically active compound and is responsible for about 15% activity of parent compound and M-III metabolite, which is inactive and responsible for 3% concentration of parent compound. There is no interference with blood constituents.[32]

The QMS-based assay can be run on selected open clinical chemistry systems; however, it is very new and more data documenting its analytical performance is needed.[33] Recently, a new radioimmunoassay method has been developed by Roche pharmaceutical, which has demonstrated good sensitivity and specificity as compared with LCMS and CMIA. This new method is called-Elecsys TAC assay, and it uses electrochemiluminescence immunoassay method.[34]

Chromatography-based methods can also be used for TDM of TAC.[35],[36],[37],[38],[39],[40] These have the advantage of estimating the drug and its active metabolite separately, and hence, they are more specific. Another advantage of liquid chromatography (LC) is that it can measure multiple drug levels simultaneously. Several LC methods are in use for measurement, i.e., LC-ultraviolet detection (LC-UV), LCMS and tandem mass spectroscopy (LCMS/MS). LC-UV method could not be used for TDM of TAC as it requires extensive sample preparation and very poor UV absorption of some compounds of TAC. The LC-UV can be used for TDM of cyclosporine, MMF, sirolimus, and everolimus. The only method possible for TAC-TDM is LCMS/MS because of its sensitivity, selectivity, and flexibility. At present, LCMS/MS is considered the best method to measure TDM of most drugs.[36],[37],[38],[39],[40] There are some limitations of LCMS/MS, i.e., high cost of instrument, need for 24 h laboratory support, and qualified technical staff.

The recent analytical service international report reveals that about 60% of the laboratory use LCMS method and 40% use IA for estimation of TAC levels. Although the HPLC-MS method has the potential to become reference method, because of variability in calibrators in different laboratories, presence of matrix effect, which can lead to erratic underestimation or overestimation of TAC level in blood and poor understanding of LCMS technique led to disparate results initially. Now similar to IA, the commercial calibrators are available, leading to less variability in results in various laboratories. Another issue with LCMS is its cost, so it can be applied only to a place, where there is sufficient load and multiple drug levels are required.[40],[41]

Cotton et al.[41] compared HPLC-MS with the two most commonly used IAs, i.e., EMIT and MEIA, and found significant differences in results from these assays. Analysis of variance revealed overestimation by 105% (94%–115%) and 117% (106%–127%), respectively, by MEIA and EMIT methods. It shows that IAs have a positive bias as compared to HPLC-MS. However, it was a single-center study and results cannot be generalized.

Recently, a rapid ultra-performance LC-with TMS (UPLC-TMS) method was validated and compared with CMIA for TAC and cyclosporine in whole blood. The results revealed that the UPLC-TMS method had a within-run and between run precision of <8% and a bias of <5%. The limit of detection was 2.0 and 2.5 ng/ml for cyclosporine A, and 0.3 and 0.4 ng/ml for TAC, respectively. The majority of results were higher for the IA than for the UPLC-TMS. The levels of cyclosporine obtained were 18% lower with UPLC-TMS method as compared to CLIA and 14% lower for TAC revealing noninterference with metabolites with this method. The newly developed rapid UPLC-TMS method was suitable for use with a large therapeutic concentration range of the analyzed immunosuppressive drugs. Sample preparation was simple and it was possible to monitor several immunosuppressive drugs simultaneously, thus significantly lowering the cost of analysis.[42]


  Pharmacogenetics Top


There is a large inter-individual difference in TAC pharmacokinetics leading to variability in doses required to achieve target concentration. The most of it is caused by genetic polymorphisms in genes encoding for biotransformation enzyme (CYP isoenzymes 3A4 and 3A5) and drug transporter (ABCB1 previously known as MDR1).[43],[44] Individuals with at least one CYP34A 1* allele are classified as expressers and those who express at least one CYP3A5 1* allele have a lower concentration of TAC with the same doses as compared to patients with CYP3A5 3*/3* expression.[43],[44],[45],[46],[47],[48],[49] One more rare type of single-nucleotide peptide (SNP) i.e., CYP3A5 6* is known to be associated with genetic polymorphism, which is located on exon 7.

In one study, it has been seen that TAC whole blood dose-adjusted trough concentration was 5.8 times lower in patients with CYP3A51*/1* genotype than patients who express CYP3A5 3*/3*. Patients with CYP3A51*/1 expression require 2.3 times higher doses as compared to patients with CYP3A5 3*/3* expression to achieve target trough concentration.[44]

Macphee et al. have shown that patients who were CYP3A5 expressers took a longer time to achieve their target levels within 2 weeks as compared to nonexpressers. There was no difference in AR, but time to rejection was earlier in expressers.[45] Another study, which compared the effect of CYP34A expression on TAC levels, found that only 20% of expressers could achieve levels >15 ng/ml in standard doses (0.1 mg/kg twice daily) as compared to 65% of nonexpressers.[46]

A recent prospective study observed the effect of CYP3A5 polymorphism on TAC pharmacokinetics in candidates for kidney transplantation. In this study, after the first dose of TAC, nonexpressers of CYP3A5 (3*/3* genotype) had an AUC 0-8 and trough levels 2.6 and 5 times higher than expressers. The study proposed that in expressers (CYP3A5 1*), TAC should be initiated at higher doses (0.15 mg/kg/dose twice daily) to achieve the target levels rapidly and nonexpressers should be initiated on lower doses (0.07 mg/kg/dose) to reduce the toxicity.[47] There are racial differences in CYP3A5 polymorphism, as about 80% of Caucasians are nonexpressers for CYP3A5 (homozygous for 3*/3*) as compared with only 30% of African–Americans.[43]

There are conflicting data about the relationship between ABCB1 gene polymorphism and TAC pharmacokinetics, with some studies supporting an effect of ABCB1 gene polymorphism and some do not.[48],[49] There are no publishes data about the MDR1 genotype effect on TAC levels.

Finally, the drug levels of TAC are increased in patients with diarrhea due to reduced activity of intestinal CYP3A and p-glycoprotein.

Some practical tips are about TAC level monitoring are summarized in [Table 2].
Table 2: Practical points regarding tacrolimus level monitoring

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  Drug Interactions Top


Drug–drug interactions are very common in kidney transplant recipients, mainly because of poly-pharmacy. These drug interactions are caused by the involvement of the CYP3A system and p-glycoprotein at intestinal and hepatic levels. The drugs (enzyme inducers or inhibitors) affect the levels by increasing or reducing oral bioavailability rather than its clearance.[50] TDM is an effective tool to monitor drug levels when these drugs are used to prevent under or overexposure of TAC.

The interaction between drugs can be pharmacokinetic or pharmacodynamics. The increase in TAC levels has been seen with antifungal agents, especially azoles; ketoconazole, itraconazole, fluconazole, macrolide antibiotics; erythromycin, clarithromycin, etc., Apart from these, other drugs increasing levels are: clotrimazole, chloramphenicol, danazol, diltiazem, antiretroviral protease inhibitors, methylprednisolone, nefazodone, theophylline, and grapefruit juice. Some other drugs suggested to increase levels in animal studies or in vitro models are: bromocriptine, cimetidine, cisapride, metoclopramide, nicardipine, nifedipine, and verapamil.

Reduction in TAC levels is seen with CYP3A inducers such as rifampicin, anti-epileptic drugs-phenytoin, phenobarbital and carbamazepine, antacids, and soda bicarbonate due to pH-mediated degradation. Long-term intake of herbal preparation St. John Worts has been associated with reduction in TAC levels.


  Use of Tacrolimus in Paediatric Population Top


TAC is the most common CNI used in pediatric kidney transplant patients. Now a days, >80% centers use TAC as induction agent, obviously because it is a stronger immunosuppressive agent and have a better side effect profile, especially cosmetic effects.[13]

The pharmacokinetics of TAC is different in the pediatric population as compared to adults in many aspects. The total body clearance of TAC in children is more, i.e., 2–3 ml/min/kg-as compared to 1–2 ml/min/kg in adults, leading to 1.5–2 times higher dose requirements in children to achieve similar drug levels. The increased clearance of TAC in children may be related to larger liver size and increased activity of CYP3A enzyme during childhood.[51]

The target AUC for TAC in the pediatric population has not been established due to the paucity of data; however, moderate correlation between AUC of LSS and trough levels has been seen (r = 0.74) in pediatric renal population initially after kidney transplantation.[52]


  Summary and Conclusions Top


TDM plays very important role in the modern era of immunosuppression as keeping immunosuppression in target range is necessary to reduce adverse effects and at the same time, maintain therapeutic efficacy. TAC is a drug of narrow therapeutic index and there is large interindividual and intraindividual variation in levels due to differences in absorption and metabolism in various persons. TAC is metabolized by CYP3A enzyme, patients who are expressers of CYP3A1*, require higher doses to achieve the same levels as compared to nonexpressers (CYP3A3*3*). TAC level monitoring is best done by LCMS/MS method, as it is more accurate and there is no interference with metabolites; however, it is labor intensive and requires good technical support. The newer IAs such as CMIA and QMS have good accuracy and are easy to operate making them good alternatives to LCMS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
the Pharmacokine...
Therapeutic Drug...
Target Trough Le...
Methods to Measu...
Pharmacogenetics
Drug Interactions
Use of Tacrolimu...
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