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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2004  |  Volume : 15  |  Issue : 2  |  Page : 119-124
C-2 Monitoring for Cyclosporin: Considerations for Implementation


School of Pharmacy, University of Auckland, Auckland, NewZealand

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How to cite this article:
Zolezzi M. C-2 Monitoring for Cyclosporin: Considerations for Implementation. Saudi J Kidney Dis Transpl 2004;15:119-24

How to cite this URL:
Zolezzi M. C-2 Monitoring for Cyclosporin: Considerations for Implementation. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2019 Oct 23];15:119-24. Available from: http://www.sjkdt.org/text.asp?2004/15/2/119/32891

   Introduction Top
Cyclosporin (CyA) has been available for more than 20 years and has represented the mainstay of immunosuppressive therapy since then. Although CyA revolutionized trans­plantation efficacy, its original formulation (Sandimmune®) was associated with serious adverse effects, including renal and hepatic dysfunction, hypertension, neurotoxicity and lymphoma. [1] For this reason, CyA has been considered as a drug with low therapeutic index, requiring individualized blood level monitoring. In addition, the oral absorption of CyA from its Sandimmune® formulation was poor and variable, ranging from 5-40%. [2] This lead to the development of the new micro-­emulsified preparation of Neoral®, which is more easily absorbed and consequently intra individual variability is significantly reduced. [3] In addition to improvement in drug delivery, the most important advantage of the Neoral® preparation was a reduction in the number of rejection episodes that occurred post transplantation. [4]

Significant improvements in the monitoring of CyA have also occurred over the past decade. CyA dosing has traditionally been based on trough blood levels (C-0) rather than area under the concentration-time curve (AUC), despite observations from researchers that C-0 correlated poorly with the extent of CyA immunosuppression or toxicity. [5],[6] Full AUC monitoring is a sensitive indicator of drug exposure as it represents the ability of an individual to absorb adequate CyA to ensure effective immunosuppression. [7] How­ever, full AUC is generally considered an impractical routine clinical parameter as it requires a series of blood samples to be taken over the full dosing interval of 12 and 24 hours, with subsequent algebraic analysis of the data to calculate the AUC value. Sparse sampling algorithms were also developed as a method of predicting AUCs without the need for a large number of blood-level measure­ments. [8] In view of these complicated methods, research was thus targeted towards the identification of the single sample that would provide the most accurate surrogate marker for full AUC. In a study of 46 renal transplant patients receiving Neoral®, two samples obtained at two and eight hours were found to account for 97% of variance in AUCs. [9] However, the authors interestingly suggested that a single sample taken at an appropriate point after dosing might be an effective means of predicting drug exposure. This approach has now been validated by researchers with the development of C-2 measurement (i.e, measurement of CyA levels two hours after administration of Neoral®) as the key strategy to CyA drug monitoring. [10],.[11]

This article summarizes the current evidence for implementation of this new strategy for cyclosporine therapeutic drug monitoring, and its implications in dosage individualization.


   Methods of CyA C-2 Monitoring Top


Various methods for the measurement of CyA C-0 concentrations have been used [12],[13] and many are still under development, but perhaps the most popular ones include high performance liquid chromatography (HPLC), radioimmunoassay techniques (RIA), and fluo­rescence polarization immunoassay (FPIA). In the past, RIA values were generally 30 to 100% higher than HPLC values because the former used polyclonal antibodies that did not differentiate the metabolites of cyclosporine from the parent compound, while HPLC was very specific, although it was more labor intensive and difficult to standardize. [14] Newer RIA assays utilize a monoclonal antibody to cyclosporine, which is more specific for the parent compound. [15] Similar to the RIA test, the FPIA utilizes monoclonal antibody, and it is also technically less challenging than the HPLC. These analytical methods differ in their accuracy and specificity for the measure­ment of the parent CyA molecule in any one sample. The differences between these methods are not constant and may be dependant upon factors such as transplant type and the time after transplantation. [16],[17] With the introduction of C-2 monitoring strategy, a reassessment of the methods used was needed and raised various concerns on how these differences could affect the blood CyA results and their interpretation. [17],[18],[19],[20]

While researchers continue to look for possi­ble answers to these concerns, laboratories around the world are increasingly adopting C-2 sampling and analytical techniques as the standard practice for CyA monitoring. [21],[22] However, measurement of CyA C-2 samples does present some methodological problems, in particular the extra step required in the dilution of the C-2 sample. Dilution is nece­ssary because the C-2 sample contains much higher concentrations of CyA than the C-0 sample. [23] Samples may be diluted 1 in 5 or 1 in 10 with CyA-free anticoagulated whole blood when the value of the CyA sample is greater than the upper calibration level of the assay used. [19] As dilution requirements may vary according to the assay used, it is recom­mended that a dilution protocol is established and validated in laboratories prior to imple­menting the CyA C-2 monitoring strategy. Additionally, it has been recommended that laboratories adopting this monitoring strategy, must implement systems that identify C-2 samples as they arrive in the laboratory, as well as a change to the reporting units to highlight that the result refers to a C-2 sample. [22],[23]


   C-2 Target Levels Top


Adoption of C-2 monitoring for CyA requires setting up the appropriate time dependent therapeutic windows for the various solid organ transplantations where it is used. Results of several studies using the Neoral® formu­lation have provided the preliminary clinical information to set up target ranges for liver and renal transplant recipients. [Table - 1] presents the target level recommendations for Neoral® C-2 monitoring to be achieved in liver and renal transplant patients according to the number of days post-transplantation. [24],[25] Although these target values have been tested in various transplant centers around the world, they still need further clinical validation. [24]

It is important to consider that the C-2 target values have been obtained in the context of dual (steroids) or triple (steroids plus azathio­prine or mycophenolate mofetil or sirolimus) immunosuppressive regimens. [24] Target levels should be reached within 3-5 days post­transplantation. Dosage optimization can be achieved by using the following formula: [26],[27]

New Neoral® dose = Old Neoral® dose x (Target C-2 level/Current C-2 concentration)

It has been recommended that de novo renal transplant patients with delayed graft function should be treated according to the standards set at the local transplant center. [24],[25],[27]

Trials in heart transplant patients have been carried out to examine the efficacy of C-2 in comparison with AUC monitoring with very similar results as those shown in renal transplantation; thus, target C-2 levels for renal transplantation may be as effective as that for heart transplantation. In pediatric transplan­tation, similar data have been demonstrated when the C-2 levels were used to monitor dosage. The preliminary C-2 target level in stable pediatric kidney transplant recipients has been suggested to be above 0.75 µg/ml. [28] Further studies must be performed to validate these results and to help identify target C-2 levels in other special patient groups.


   Patient Management Using C-2 Monitoring Top


Except for accuracy in sampling time, the overall recommendations for CyA blood collection remain the same for C-2 monitoring. The recommended sample type is EDTA anticoagulated whole blood. [12] Traditionally, this has been collected into glass tubes (because of the possibility of CyA being adsorbed onto plastic), although plastic tubes have also been shown to be suitable. [29],[30] Peripheral veins are the preferred sites for blood sampling, as higher concentrations have been reported when samples were collected from central venous catheters. Caution in interpolation of CyA concentrations has thus been advocated, particularly if samples are drawn through narrow catheters in patients who have high blood lipid concentrations. [30],[31]

C-2 monitoring requires a timed blood sample outside the regular sampling schedule for transplant recipients. Consequently, trans­plant centers need to establish C-2 monitoring protocols to appropriately handle their patients. It is ideal and highly recommended by centers with experience in implementing C-2 monitoring that the entire transplant team (physicians, nurses, pharmacists, phlebotomists and the laboratory members) participate in the development of the protocol. [23] The protocol should be designed to ensure that patients take their dose on time, the blood samples are drawn 2-hours post dose (±10 min), [21],[23],[25] sampling timing is documented, and that C-2 and C-0 samples are differentiated with suitable labeling all the way through to final reporting. [23] Accurate sampling and dosing time are thus critical in C-2 monitoring and cannot be more emphasized. Small errors in sampling or dosing time have the potential to result in significant differences in the measured CyA concentration. [21]


   The Role of the Pharmacist Top


The implementation of the C-2 monitoring strategy is an ideal opportunity for pharmacists to demonstrate their value on the transplant team. As other allied health professionals, pharmacists can play an important role in optimizing CyA regimens with the use of C-2 monitoring by numerous functions: educate patients about this new management technique, assist physicians and nurses in the interpretation of CyA C-2 levels, recommend individualized drug therapy accordingly, and provide suitable drug information specifically differentiating C-2 and C-0 monitoring stra­tegies for the various patient populations for which CyA is prescribed.

Particular emphasis should be given to the education of patients, while they are in the ward. The clinical pharmacist should educate patients about the outcome benefits of C-2 monitoring and the need to have their blood sample taken 2 hours (±10 min) post dose. Providing verbal and written information about C-2 monitoring and the procedure to be adopted for sampling after discharge, is essential in promoting this strategy among patients. Patients who were previously moni­tored by cyclosporine C-0 may require more extensive counseling than de novo patients to understand the difference between the two techniques. [27] Continuous communication between in-patient and out-patient settings, including community pharmacies, should be facilitated by pharmacists to assure under­standing of the principles of C-2 monitoring is continued after the patient is discharged from hospital.

Clinical pharmacists can use their sound background on pharmacokinetics to assist researchers in various issues of C-2 moni­toring that still need to be addressed, such as the role of concomitant immunosuppressive drugs (such as sirolimus, mycophenolate mofetil or monoclonal antibodies versus interleukin-2 receptor) when CyA is dosed according to C-2 levels, drug interactions, or whether C-2 monitoring is applicable to other generic forms of CyA. [24]

Finally, drug information pharmacists must familiarize themselves with the concepts of C-2 monitoring in order to provide appro­priate information to all the members of the transplantation team, as well as the patients. Many transplant centers have post-transplant pharmacy management programs, which need accessibility to knowledgeable and updated drug information centers to assure that conti­nuity of care is provided to these patients. Thus, drug information pharmacists need to familiarize themselves not only with the concepts of C-2 monitoring, but also with the implementation process of this new technique in their institution, so that the correct information on CyA monitoring is provided to the requester, according to the type of transplant and the indication for which CyA has been prescribed.


   Conclusion Top


CyA is a critical drug for which individua­lization of dosage by therapeutic drug moni­toring is essential. Current evidence suggests that a single concentration taken two hours after CyA administration (C-2) with the microemulsion formulation (Neoral®) better predicts exposure and events than the trough concentration (C-0). This strategy appears to be particularly useful to achieve adequate immunosuppression during the first week after transplantation. Time-dependent C-2 target values have been proposed for liver and renal transplant recipients, and are being investigated for other patient populations, but require further prospective validation.

The successful implementation of C-2 monitoring strategies require the active parti­cipation of the multidisciplinary transplant team for each institution to assure that the patients are sampled on time, that the analyzed samples have on-site validated dilution guidelines, that the patients are managed following established protocols and according to the recommended C-2 target levels. Patient education and adequate communication in the out-patient settings are also essential to make this new option of CyA monitoring safe and efficient.

 
   References Top

1.Kahan BD. Cyclosporine. New Engl 1989; 321:1725-38.  Back to cited text no. 1    
2.Fahr A. Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 1993;24:472-95.  Back to cited text no. 2    
3.Kovarik JM, Mueller EA, Niese D. Clinical development of a cyclosporine microemulsion in transplantation. Ther Drug Monit 1996;18:429-34.  Back to cited text no. 3    
4.Canadian Neoral Renal Transplantation Study Group. Absorption profiling of cyclosporine microemulsion (Neoral) during the first 2 weeks after renal transplantation. Trans­plantation. 2001;72:1024-32.  Back to cited text no. 4    
5.Lindholm A, Welsh M, Rutzky L, Kahan BD. The adverse impact of high cyclosporine. Clearance rates on the incidences of acute rejection and graft loss. Transplantation 1993;55:985-93.  Back to cited text no. 5    
6.Schroeder TJ, Hariharan S, First MR. Variations in bioavailability of cyclosporine and relationship to clinical outcome in renal transplant subpopulations. Transplant Proc 1995;27:837-9.  Back to cited text no. 6    
7.Mahalati K, Belitsky P, West K, et. al. Appro­aching the therapeutic window for cyclosporine in kidney transplantation: a prospective study. J Am Soc Nephrol 2001;12:828-33.  Back to cited text no. 7    
8.Mahalati K, Belitsky P, Sketris I, West K, Panek R. Neoral monitoring by simplified sparse sampling area under the concentration­time curve: its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation. Transplantation 1999;68:55-62.  Back to cited text no. 8    
9.Johnston A, Kovarik JM, Mueller EA, Holt DW et al. Predicting patients' exposure to cyclosporin. Transplant Int 1996;9(suppl 1):S305-7.  Back to cited text no. 9    
10.Nashan B, Cole E, Levy G, Thervet E. Clinical validation studies of Neoral C (2) monitoring: a review. Transplantation 2002;73(9):S3-11  Back to cited text no. 10    
11.Dunn S, Falkenstein, K, Cooney G. Neoral C (2) monitoring in pediatric liver transplant recipients. Transplant Proc 2001;33:3094-5.  Back to cited text no. 11    
12.Oellerich M, Armstrong VW, Kahan B, et al. Lake Louise Consensus Conference on cyclosporine monitoring in organ trans­plantation: report of the consensus panel. Ther Drug Monit 1995;17:642-54.  Back to cited text no. 12  [PUBMED]  
13.Morris RG, Lam AK. Cyclosporin monitoring in Australasia: survey of laboratory practices in 2000. Ther Drug Monit 2002;24:471-8.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Carruthers SG, Freeman DJ, Koegler JC, et al. Simplified liquid-chromatographic analysis for cyclosporin A, and comparison with radioimmunoassay. Clin Chem 1983;29:180-3.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Schutz E, Svinarov D, Shipkova M, et. al. Cyclosporin whole blood immunoassays (AxSYM, CEDIA, and Emit): a critical overview of performance characteristics and comparison with HPLC. Clin Chem. 1998; 44:2158-64.  Back to cited text no. 15    
16.Steimer W. Performance and specificity of monoclonal immunoassays for cyclosporine monitoring: how specific is specific? Clin Chem 1999;45:371-81.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Holt DW, Johnston A, Kahan BD, et al. New approaches to cyclosporine monitoring raise further concerns about analytical techniques. Clin Chem 2000;46:872-4.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Legatt DF, Coates JE, Simpson AI, et al. A comparison of cyclosporine assays using sequential samples from selected transplant patients. Clin Biochem 1994;27:43-8.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Johnston A, Chusney G, Schutz E, et al. Monitoring cyclosporine in blood: between­assay differences at trough and 2 hours post­dose (C2). Ther Drug Monit 2003;25:167-73.  Back to cited text no. 19    
20.Johnston A, Lee TD, Chusney GD, et. al. New approaches to Neoral monitoring: methodological implications. Ther Drug Monit. 2001;23:465. (Abstract from 7th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology, Washington DC, September 2001).  Back to cited text no. 20    
21.Morris RG, Ilett KF, Tett SE, et al. Cyclosporin monitoring in Australasia: 2002 update of consensus guidelines. Ther Drug Monit 2002;24:677-88.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Holt D, Armstrong VW, Griesmacher A, et al. International Federation of Clinical Chemistry/International Association of Therapeutic Drug Monitoring and Clinical Toxicology Working Group in immuno­suppressive drug monitoring. Ther Drug Monit 2002;24:59-67.  Back to cited text no. 22    
23.Cole E, Midtvedt K, Johnston A, et al. Recommendations for the implementation of Neoral C (2) monitoring in clinical practice. Transplantation 2002;73(9):S19­22.  Back to cited text no. 23    
24.Oellerich M, Armstrong VW. Two-hour cyclosporine concentration determination: An appropriate tool to monitor Neoral therapy?. Ther Drug Monit 2002;24(1):40-6.  Back to cited text no. 24    
25.Novartis Pharma Schweiz A. C-2 monograph. C-2 monitoring with Neoral(R). Available at: http://www.transplantationschweiz.ch/e/san dimmun/Scientific_Monograph.pdf. Accessed 15/12/2003, 2003.  Back to cited text no. 25    
26.Levy GA. C2 monitoring strategy for optimising cyclosporine immunosuppression from the Neoral formulation. BioDrugs 2001;15(5):279-90.  Back to cited text no. 26    
27.Pape L, Lehnhardt A, Latta K, et al. Cyclosporin A monitoring by 2-h levels: preliminary target levels in stable pediatric kidney transplant recipients. Clin Transplant 2003;17(6):546-8.  Back to cited text no. 27    
28.Faynor SM, Robinson R. Suitability of plastic collection tubes for cyclosporin measurements. Clin Chem 1998;44:2220-1.  Back to cited text no. 28  [PUBMED]  [FULLTEXT]
29.Andrews DJ, Cramb R. Cyclosporin: revisions in monitoring guidelines and review of current analytical methods. Ann Clin Biochem 2002;39(Pt 5):424-35.  Back to cited text no. 29    
30.Kami M, Yamamoto K, Kanda Y, et al. Influence of blood sampling sites on measurement of blood cyclosporine con­centration. Transplantation 2000;69:1750-2.  Back to cited text no. 30  [PUBMED]  [FULLTEXT]
31.Kahan BD, Keown P, Levy GA, Johnston A. Therapeutic drug monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002;24(3):330-50.  Back to cited text no. 31    

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Correspondence Address:
Monica Zolezzi
Lecturer, School of Pharmacy, University of Auckland, Private Bag 92019, Auckland
NewZealand
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PMID: 17642761

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