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The introduction of the microemulsion formulation of cyclosporine (Neoral, Novartis Pharmaceutical Corporation) lead to renewed interest in the way in which cyclosporine levels are monitored and dose adjusted. Cyclosporine has a narrow therapeutic window requiring close monitoring to ensure adequate immunosuppression while avoiding nephrotoxicity. Neoral has significant benefits over the original cyclosporine formulation with a more predictable absorption profile and improved clinical outcomes (1–3). Cyclosporine exposure, as measured by area under the concentration curve, has been shown to correlate well with clinical outcomes (4, 5). Pharmacokinetic studies have demonstrated a poor correlation between traditional trough level (predose; C0) monitoring and cyclosporine exposure measured in this way, casting doubt on the use of C0 monitoring (6–8). Furthermore, C0 levels do not appear to differentiate those patients at risk of acute rejection (8). Analysis of absorption profiles has shown that the majority of intra- and interpatient variability in blood levels occurs in the early phase of absorption, mainly the first 4 hr (9). This measure of cyclosporine exposure during the first 4 hr postdose might lead to more accurate dosing and improved clinical outcomes (Fig. 1).
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FIGURE 1.:
The cyclosporine absorption curve. C0, trough (predose) level; C2, 2-hour level; Cmax, maximum blood level; AUC0-4h, area under the concentration time curve for the first 4 hr.
The use of an abbreviated area under the curve estimation from the first 4 hr postdose (AUC0-4h) to monitor cyclosporine levels has been reported (8, 10, 11) and the AUC0-4h has been shown to correlate well with the risk of acute rejection in renal transplant recipients (8). Despite this apparent clinical benefit, uptake of AUC0-4h monitoring within the transplant community has been limited as it is largely impractical outside of the clinical trial setting. Multiple and accurately timed blood samples are required, and the AUC must then be calculated using a mathematical formula. Such intricacies add to both the time and cost commitment of monitoring. These limitations have lead to interest in finding a single time point which better correlates with the area under the curve than the trough level (C0).
Pharmacokinetic studies have demonstrated that the cyclosporine level at 2 hr postdose (C2) is the best single time point predictor of AUC0-4h in kidney (7), liver (12, 13), heart (14), and lung (15) transplant recipients. Interpatient variability of C2 levels is lower than that of trough levels (7). Furthermore, pharmacodynamic studies demonstrate excellent correlation between calcineurin inhibition and blood levels of cyclosporine, with maximum inhibition at around 2 hr postdose (16). Variability in the expression of the cytokine interleukin (IL)-2 decreases with increased blood cyclosporine concentrations and hence error in the estimation of the immunosuppressive effects induced by cyclosporine will be less with C2 than trough measurements (17).
In the clinical setting, several retrospective analyses have demonstrated correlations between the risk of acute rejection and C2 levels measured in patients dose adjusted according to C0. C2 levels were shown to be highly predictive of acute rejection in de novo renal patients (10, 18), but in cardiac transplant recipients the correlation was weaker (19, 20). In hepatic transplant recipients, the maximum cyclosporine level (Cmax) shows a strong correlation with freedom from rejection (21); C2 is taken as an estimate of Cmax. These observations suggest that adjusting cyclosporine dose according to C2 levels may optimize cyclosporine exposure and improve clinical outcomes.
A number of comparative studies have now been performed investigating the application of C2 monitoring in organ transplantation and to assess clinical outcomes. This review aims to systematically appraise the quality and findings of these studies in order to assess the clinical benefits of C2 monitoring of cyclosporine levels.
METHODS
A systematic literature search was performed using the Cochrane Central Registry of Controlled Trials, Ovid Medline and Embase, the National Center for Biotechnology Information’s Pubmed Medline, and clinical trial registries (clinicaltrials.gov, current controlled trials, the national research register, and the Cochrane renal group register). Search terms were broad and equivalent for each database, specifically for studies investigating C0 or C2 monitoring in adult human solid organ transplantation from 1990 to present. This start date was selected as it predates the introduction of the Neoral form of cyclosporine. The initial search strategy incorporated the randomized controlled trial search filter from the Cochrane group (22); however, this was removed in the final search for reasons described below.
Initial search results were reviewed for duplicates. Titles and abstracts were then reviewed to select studies based upon predefined inclusion criteria. These defined a population of adult solid organ transplant recipients receiving the microemulsion formulation of cyclosporine, in which a direct comparison was made between a cohort of patients monitored by C0 levels, and a cohort monitored by C2 levels. Initially these inclusion criteria limited the search to randomized controlled trials, but due to the lack of such trials in the published literature, the criteria were broadened to include any observational or experimental study meeting the other inclusion criteria and the search repeated. Studies in which stable patients were switched from C0 to C2 monitoring and followed up were included, as long as a comparison with baseline (C0 monitoring) was made. Studies with no comparison and those in which doses were not adjusted according to C2 levels were excluded. Full texts of potentially relevant studies were then obtained in order to make a final decision on inclusion in the review. Reference lists of relevant studies and reviews were also checked for any studies that might have been missed.
The quality of the studies included in the review were assessed both for general parameters of a good quality study such as an adequate description of randomization, adequate concealment of randomization, sample size calculation, adequate description of withdrawals, analysis based on intention to treat and parameters specific to these studies such as a description of target ranges for C0 and C2 levels, and dose adjustment based on target ranges.
RESULTS
The database search generated 5907 potentially relevant citations after removal of duplicates. After review of titles and abstracts, the full text of 182 papers were assessed. Twenty-eight papers were identified to be included in the final review (13, 14, 23–48). One further reference (a conference abstract) was identified from the reference lists of these studies (49). Two potentially relevant unpublished trials were identified from the trial registries and authors contacted requesting further information. One author replied with preliminary results (50). Two papers contained duplicate reports of the same data at different time-points and are included as a single study (36, 37). A total of 29 studies were included in this analysis.
The quality of these 29 identified studies is described in Supplemental Tables 1–4, available for viewing online only. In summary, only 10 were randomized controlled trials. Of these, four (40%) describe an adequate method of random sequence allocation and only two (20%) describe adequate concealment of the randomization sequence from investigators. Five of the 29 included studies (17%) have a sample size calculation. Thirteen studies (45%) gave a description of withdrawals but only eight (28%) used this information to perform analysis on the basis of intention to treat.
Knowledge of the target ranges used to adjust cyclosporine doses is important in analyzing the reported data as different target ranges can affect clinical outcomes. Despite this, two studies (7%) did not report their C2 target ranges for monitoring and eight (28%) did not report the C0 target ranges. Target ranges for the included studies are shown in Supplemental Tables 5–8, available for viewing online only. Further attention was given to whether or not the protocol for adjusting doses when levels were outside of the target ranges was specified. This was deemed an important factor in the quality of a study as a strict dose adjustment protocol is less likely to introduce bias than leaving individual clinicians to adjust dose as they see fit, particularly in nonblinded studies. Of the included studies, only 10 (34%) clearly describe a protocol for dose adjustment.
C2 Monitoring in Renal Transplant Recipients
De Novo Patients
A recent randomized, single-center study of good quality from Helsinki has investigated the application of C2 monitoring in de novo renal transplant patients (23) (Table 1). Patients were randomized to be monitored by C0 or C2 levels for 20 days posttransplantation; after this period all patients reverted to C0 monitoring. There was no significant difference in the number or severity of rejection episodes. Despite dose adjustments, 72% of C2 monitored patients did not reach the C2 target range by day 3 posttransplant, with 45% failing to reach the target range by day 5. However, there was no significant increase in rejection rate in those patients not achieving target levels by day 3 or 5.
TABLE 1: Outcomes of studies in renal transplantation
Paired measurements demonstrated trough levels significantly higher than the target range in patients monitored by C2, and mean cyclosporine dose was 56% higher in the C2-monitored cohort during the first 20 days. Despite this, creatinine clearance, serum creatinine, and the incidence of delayed graft function was similar in both groups. The increased dose in C2-monitored patients may reflect difficulty reaching the early target levels, which are higher than other studies immediately posttransplant.
The only other published randomized trial of C2 monitoring in de novo renal transplantation is from China (24). The initial C2 target range in this study for months 0–3 was lower than that of the Helsinki study, and reduced over the follow-up period of 12 months (Supplemental Table 5, available for viewing online only). In contrast to the Helsinki study, rejection rates were significantly higher in the C0-monitored cohort, despite the lower C2 range. The reason for this high rejection rate in the C0-monitored cohort is unclear; the authors do not state their C0 target range and no information is given as to the speed of achievement of target levels. An increase in serum creatinine at 1 year in the C0-monitored cohort is also noted.
The remainder of the evidence in de novo renal transplant patients comes from six nonrandomized studies (25–30). None of these studies support a significant reduction in biopsy-proven rejection rates in C2-monitored patients. Only one other study, by Paydas et al. (25), supports the findings by the Chinese group of a decline in renal function in the C0-monitored group over the study period, although this study is of very limited quality with only 23 of 37 patients available at 36 month follow-up.
Three of these nonrandomized studies (26, 28, 30) support the finding of the Helsinki study that mean cyclosporine dose in the early posttransplant period is significantly higher in a cohort monitored by C2. A sequential cohort study utilizing a quadruple immunosuppressive regimen with antibody induction (27) contradicts this finding, with a significantly lower cyclosporine dose requirement in the C2-monitored patients. This may be explained by lower C2 target levels than other studies (Supplemental Table 5, available for viewing online only), and perhaps lower initial target ranges may be appropriate when antibody induction is used.
Stable Patients
The evidence for the application of C2 monitoring in stable renal transplant patients is more limited. The only randomized controlled trial to date involved 70 patients more than 3 months posttransplantation, randomized to continue monitoring by C0 or switch to C2 monitoring (31). Acute rejection rates and incidence of nephrotoxicity were similar between the two cohorts. The study demonstrated a greater number of patients in the C2 group with dose reductions than in the control group during the study period (34.3% vs. 14.3%, P=0.02).
The remaining evidence for C2 monitoring in stable renal transplant recipients comes from before-and-after studies in which patients are switched from C0 to C2 monitoring regimens and changes in clinical parameters followed (32–35). Despite the limitations of this type of study, consistency of results is good and in agreement with the randomized trial described above. A mean cyclosporine dose reduction of around 20% is seen in all studies reporting this outcome (32, 33, 35). Reduction in dose was not accompanied by an increase in acute rejection rate in any study, with rates remaining low throughout, ranging from 0% (32, 33) to 1.6% (34). Despite this reduction in cyclosporine exposure, no paper reported a significant improvement in renal function during the study period. Citterio et al. (32) describe a decrease in the mean number of antihypertensive medications used after switching to C2 monitoring, albeit with no reduction in mean blood pressure.
C2 Monitoring in Hepatic Transplant Recipients
De Novo Patients
The largest study to date comparing C2 and C0 monitoring strategies randomized 307 de novo hepatic transplant recipients for the first 3 months after surgery in a multicenter trial (36, 37) (Table 2). Although there was no difference in treated acute rejection rate between the two groups, there were fewer histologically moderate and severe rejection episodes in the C2-monitored group (15 vs. 35, P=0.01). No difference in renal or hepatic function, or in the rates of other adverse events, was seen between groups at the end of 3 months.
TABLE 2: Outcomes of studies in hepatic transplantation
As has been shown in renal transplantation, achieving desired C2 targets in the early period posttransplantation proved difficult, with only 10.8% of C2-monitored patients achieving the target range by day 3 as compared to 56.3% of C0-monitored patients. The rejection rate in patients achieving the C2 target range within 3 days was lower than those reaching target levels by day 7 (12.5% vs. 26.3%, P<0.03). C2-monitored patients received significantly higher doses of cyclosporine in the first month after transplantation (12.9 mg/kg/day vs. 10.3 mg/kg/day, P=0.001).
The monitoring strategies were continued for 1 year and follow-up data reported (37). The difference in rejection rates remained nonsignificant and no difference in adverse event rates was seen. The mean daily cyclosporine dose at 1 year was similar, suggesting that the early higher doses in the C2 group are not maintained.
A smaller study from China supports these findings (38). Patients were randomized to be monitored either by C0 levels, “low” C2 levels or “high” C2 levels (Supplemental Table 6, available for viewing online only). No difference in rejection rates was seen between the groups, and although renal function was significantly impaired in the high C2 group compared to low C2, there was no difference when the low C2 patients were compared with the C0 monitored cohort. In contrast to the trial above, mean cyclosporine dose at the end of the study was significantly lower in the low C2-monitored cohort when compared with the C0-monitored patients (2.51 vs. 3.11 mg/kg/day). However, this led to the mean paired C0 level in the low C2-monitored cohort falling below the C0 target range. The size of this study is small and it is possible that, in a larger cohort followed up for a longer period of time, this lower cyclosporine level may lead to an increase in rejection episodes.
Comparable results were achieved in a nonrandomized prospective study of 108 consecutive hepatic transplant patients (39). There was no difference in rejection rates between the C0 and C2 groups (26% vs. 18%, P=NS) and no difference in the rate of renal dysfunction. In contrast to the multicenter trial above, severity of acute rejection episodes did not differ between groups.
Stable Patients
The only randomized trial of C2 monitoring in stable hepatic transplant patients is a small study of 35 patients greater than one year posttransplantation (13). Patients were randomized to one of three groups: to continue monitoring by C0 levels, C2 monitoring with a high target level, or C2 monitoring with a low target level (Supplemental Table 6, available for viewing online only). A total of 82% of the patients in the low C2 level group achieved clinical benefit (defined as no acute rejection or increase in serum creatinine at month 7), compared to 37.5% in the C0-monitored group (P=0.03) and 23% in the high C2-monitored group (P=0.01). However, this composite measure of outcome does not take into account the magnitude of the change in renal function, which is in fact very small in both the C0 and low C2 groups. There was no significant change in mean serum creatinine in either the C0 or the low C2 level group during the study period; only the group monitored with high C2 levels show a clear increase in serum creatinine (+24 μmol/L). Acute rejection rates, liver biochemistry, and blood pressure did not differ. At the end of the study, the mean cyclosporine dose in the low C2-monitored group was 35% lower than that in the C0-monitored patients (P=0.002). These results demonstrate a clear benefit of a lower C2 target range, with the only benefit of C2 monitoring over C0 monitoring being a reduction in mean cyclosporine dose over the study period.
A further small study has investigated switching a cohort of 31 stable liver transplant patients from C0 to C2 monitoring (40). A significant proportion of patients (68%) required a dose reduction on switching, and in those in whom dose reduction was undertaken there was an 11.6% improvement in creatinine clearance (P=0.016). Importantly, it was noticed that 13 of 21 patients (61.9%) in whom the dose was lowered at the start of C2 monitoring had repeat AUC measurements below the target range after reduction (and were therefore below the lower target level with C0 monitoring). Two of these patients developed acute rejection during the study period. Although this is a small study with a limited number of patients, these findings suggest that despite C2 levels within the target range, C0 levels may be below target leading to a reduction in immunosuppression with very minimal clinical benefit.
C2 Monitoring in Cardiac Transplant Recipients
De Novo Patients
A recently reported randomized trial has shown no clinical benefit of C2 monitoring in de novo cardiac patients over the 6 months posttransplantation (49) (Table 3). Forty patients were randomized to C2 or C0 monitoring from day 7 posttransplantation. No difference in renal function, blood pressure, number of antihypertensive medications, incidence of acute rejection, infection rates, or lipid levels were demonstrated between the two cohorts. The total cyclosporine dose was lower in the C2-monitored group at 6 months (300 mg vs. 400 mg, P=0.03).
TABLE 3: Outcomes of studies in cardiac transplantation
Other evidence comes from two sequential cohort studies comparing C2 with C0 monitoring directly (42) and combined C0 and C2 monitoring with C0 monitoring alone (41). Neither of these studies demonstrated a significant difference in acute rejection rates between groups. As has been described in renal transplant patients, the combined C2- and C0-monitored group in the study by Barnard et al. (41) had significantly fewer moderate or severe rejection episodes (grade ≥3a) than those monitored by C0 alone (5% vs. 11%, P=0.002). However, these patients had higher serum creatinine levels and lower glomerular filtration rates at both 3 and 12 months posttransplantation, which may reflect the higher mean cyclosporine dose at 3 months (332.3±1212 mg/day vs. 245.5±77.52 mg/day, P<0.008). This contrasts with the lower dose seen in the randomized trial described above and in the report by Cantarovich et al., who demonstrate a significantly lower mean dose in C2-monitored patients at 3 and 6 months (42).
Stable Patients
The two earliest studies of C2 monitoring in stable cardiac transplant patients were performed by Cantarovich et al. (14, 43) in Montreal. In the first of these studies (14), 30 patients one year or more after surgery receiving the Sandimmune formulation of cyclosporine were switched to the Neoral formulation and randomized to be monitored by C0 or C2. All patients in the C2 group required a dose reduction after conversion to Neoral leading to a significantly lower mean cyclosporine dose at the first follow-up visit (4–6 weeks after switching). Perhaps as a result of this lower cyclosporine exposure in the C2-monitored group, serum creatinine was lower in this group at 4–6 weeks. There was, however, no difference in creatinine clearance at this point. After 4–6 weeks, all patients were monitored by C2 levels and the target range was increased to 300–600 μg/L (based upon clinical outcomes and pharmacokinetic profiles). Patients were then followed-up for a mean of 5 months. At the end of this period, the differences in serum creatinine between the groups were no longer apparent.
The same group also studied a cohort of 114 stable cardiac transplant patients in a sequential study design (43). For the initial study period patients were monitored by C2 levels, with a switch to C0 monitoring at 1 year. The change in serum creatinine seen in each period was significantly different, with an increase seen after switching to C0 monitoring. No differences in mortality, acute rejection rate, or left ventricular ejection fraction were seen between the two study periods. Using a composite measure of outcome, 69.3% of patients achieved clinical benefit during the initial period of C2 monitoring, compared to 43.3% during the C0-monitoring period (P=0.00001).
More recently, a larger randomized trial of 125 stable patients has been reported (44). There were no suspected episodes of rejection during the study period, and there was no difference in the changes in creatinine clearance seen (+0.54 vs. −0.16 ml/min, P=0.61). Both groups demonstrated a cyclosporine dose reduction during the study period, which was greater in the C2-monitored group (26 mg/day vs. 11 mg/day, P=0.0025). Another recent study by Delgado et al. provides further support for these findings (45). After switching from C0 to C2 monitoring, there was no increase in acute rejection rates, and mean creatinine and creatinine clearance were unchanged during the follow-up period.
C2 Monitoring in Lung Transplantation
De Novo Patients
Morton et al. have compared sequential matched groups of 18 de novo bilateral lung transplant recipients monitored by trough or C2 levels (46) (Table 4). Vascular or bronchial rejection rates did not differ between the two groups at 3 months. Patients monitored by C0 levels had a greater rise in serum creatinine from baseline than those monitored by C2 levels (90±54% vs. 33±23%, P<0.001), although mean serum creatinine at 3 months was not significantly different. The initial C0 target of 450 μg/L in this study is significantly higher than used in transplantation of other organs, which may lead to a detrimental effect on renal function in the early postoperative period.
TABLE 4: Outcomes of studies in lung transplantation
This cohort of patients has also been included in a larger study by the same group, in which 50 de novo lung transplant patients were monitored by C2 levels and compared to an historical control cohort of 338 patients monitored by C0 (47). Freedom from rejection was higher at 1 year posttransplant (69% vs. 41% in the control cohort, P=0.001) and freedom from bronchiolitis obliterans syndrome (BOS) was increased at all time points posttransplantation in C2-monitored patients. Although these results provide further longer-term support for C2 monitoring in lung transplant recipients, they must be interpreted with some degree of caution due to the historical nature of the control cohort. These patients were transplanted up to 12 years earlier than those in the C2 cohort, and it is conceivable that other improvements in care during this period contributed to the improvement in clinical outcome.
Preliminary data from a methodologically sounder study have shown considerably smaller clinical benefits (50). This randomized controlled trial of 69 patients prospectively compared three cohorts of de novo lung transplant patients monitored by C0, low C2, and high C2 levels over a 6-month period. Both C2-monitored groups showed a trend towards reduced rejection episodes, but this did not achieve statistical significance in either group (biopsy-proven rejection rates per 100 days 0.40, 0.31 and 0.13 in C0, low C2 and high C2 groups, respectively, P=NS). Renal function was improved in the low C2 arm over C0-monitored patients at 3 months (creatinine clearance 74.6 ml/min vs. 59.3 ml/min, P=0.02), but this difference was not maintained at 6 months. Both C2 arms of the study had a lower mean cyclosporine dose than the C0 monitored cohort at 6 months. Mean C0 levels in the C2 monitored patients at 6 months were below the target range (200–250 μg/L). Despite this reduction in C0 levels to below threshold, a decrease in rejection rates was seen in these groups supporting a benefit from C2 monitoring not related to overall cyclosporine dose.
Stable Patients
The only reported study in stable lung transplant recipients switched 15 patients with impaired renal function from C0 to C2 monitoring (48). Although a mean dose reduction was possible, leading to an improvement in serum creatinine at 12 months, it is unlikely that these results can be generalized to a population with normal renal function.
DISCUSSION
Much indirect evidence, both pharmacological and clinical, has been cited to suggest that C2 monitoring should confer a benefit over trough level monitoring of cyclosporine. Despite such theoretical advantages and the publication of consensus statements in favor of C2 monitoring strategies (51), it has been noted previously that the direct evidence for a benefit of C2 monitoring over trough levels is limited and of poor quality (52). The limited benefits shown in these studies have led to some centers abandoning the strategy (53).
The present systematic review demonstrates a lack of good quality, randomized studies comparing trough and C2 monitoring strategies. The majority of studies discussed here are observational or nonrandomized experimental studies. Even those studies employing randomization display limitations in their design and reporting. Such findings are not limited to the topic in hand: previous authors have described a lack of methodological quality in trials in organ transplantation (54, 55). The results from the studies included in this review demonstrate a great deal of heterogeneity, which makes firm conclusions difficult to reach. The poor quality of the studies also precludes meta-analysis.
Studies in both renal and hepatic transplant recipients demonstrate difficulty in reaching initial C2 target levels (23, 30, 36). This difficulty may explain the higher cyclosporine doses seen in these studies in the early posttransplant period, and may explain why the theoretical benefits of C2 monitoring seen in retrospective analyses and pharmacokinetic studies are not borne out in prospective trials. Despite the higher initial doses seen, there is no clear evidence of any long-term adverse side effects. Although overall rejection rates in these de novo patients do not appear to be affected by monitoring strategy, trials in both hepatic (36, 37) and cardiac transplant recipients have suggested a possible reduction in severity of rejection episodes. The absence of larger trials, with longer follow-up periods, makes interpretation of rejection data difficult due to a lack of statistical power. Indeed, Kyllönen et al. (23) suggest that in order to be confident of a reduction in rejection rate from 18% to 9%, a sample size of more than 500 patients would be required.
In stable transplant recipients, rejection rates with modern immunosuppressive regimens are low regardless of monitoring strategy and other long-term detrimental effects of drug therapy become more important, such as renal dysfunction. The majority studies in renal, hepatic, and cardiac transplant patients demonstrate C2 levels higher than targets on switching to C2 monitoring, allowing a dose reduction. Although this may have an economic benefit in terms of the overall cost of immunosuppression, there is very little data to suggest any short-term clinical benefit of these dose reductions. Indeed, lowering the cyclosporine dose to reflect C2 levels may even reduce immunosuppression to below adequate levels (40). However, it is possible in the longer-term that this reduction in cyclosporine exposure may decrease the risk of chronic allograft nephropathy (CAN). Indeed, the incidence of CAN is directly related to cyclosporine exposure and the median time to onset of CAN is 3 years, with increasing incidence to 10 years and beyond (56). The longest follow-up period in the currently identified studies is 40 months.
There is considerably less data available for lung transplant recipients. Recent studies in de novo patients have shown some promising benefits with C2 monitoring, with small reductions in acute rejection rates and the incidence of bronchiolitis obliterans despite lower cyclosporine doses. The only study in stable lung transplant recipients to date recruited a small number of patients on the basis of impaired renal function, so cannot be generalized to the transplant population as a whole.
It is worthy of note that single-point monitoring strategies, either trough or C2 levels, may not be sufficient for all patients. A number of patients demonstrate either delayed or inadequate absorption of cyclosporine and in order to differentiate between the two, multiple-point sampling strategies may be required. For example, delayed absorption is seen in almost half of liver transplant patients in the early posttransplant period (57). Consensus guidelines recognize this limitation of a single-point strategy, and recommend the sampling of additional time-points or AUC0–4h monitoring in the first week posttransplant, in those patients requiring unusually high cyclosporine doses and when the ratio of C2:C0 is low (58).
Target C2 levels are dependant on concomitant immunosuppression (58). Indeed, with the more recently introduced agents such as everolimus and sirolimus cyclosporine doses are often minimized especially in the stable phase. With the lower doses used in these regimens, the importance of therapeutic drug monitoring may be diminished.
C2 monitoring has practical disadvantages which must be addressed when considering any potential clinical benefit. As blood samples for C2 levels are taken during a more dynamic phase of cyclosporine absorption than those for trough levels, accurate timing of samples is essential. Consensus guidelines suggest that there is a 15-min “window of opportunity” before and after the 2-hr point in which samples should be taken, although more recent evidence has suggested that this window may be as small as 10 min before and after to give an acceptable (±20%) error around the true C2 value (51, 59). Although such strict timing requirements may be adhered to in the context of a clinical trial, it is likely that problems will arise in the setting of a busy outpatient clinic. Any economic benefits resulting from a mean dose reduction in stable patients must be offset by the increased logistical and staffing costs incurred in implementing a C2-monitoring strategy.
In conclusion, the quality of the evidence directly comparing C0 and C2 level monitoring to guide cyclosporine dosing in transplant patients is poor. The theoretical advantages of C2 monitoring, as a reflection of AUC, have not been translated in to clear short-term clinical benefits. In the longer-term, the reduction in cyclosporine dose seen in some stable patients may reduce the risk of chronic allograft nephropathy. Better quality evidence from well-designed, randomized trials with longer follow-up periods is required before C2 monitoring can be recommended due to the practical limitations in its implementation outside of the trial setting.
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