The value of C2 monitoring in stable renal allograft recipients on maintenance immunosuppression

Gunilla Einecke1, Ingrid Mai2, Lutz Fritsche1, Torsten Slowinski1, Johannes Waiser1, Hans-Hellmut Neumayer1 and Klemens Budde1

1Department of Nephrology and 2Department of Clinical Pharmacology, Charité, Humboldt University, Berlin, Germany

Correspondence and offprint requests to: Gunilla Einecke, Department of Nephrology, Charité, Humboldt University, Schumannstrasse 20–21, D-10117 Berlin, Germany. Email: gunilla.einecke{at}charite.de



   Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Cyclosporin A (CyA) is a drug with a narrow therapeutic window and highly variable pharmacokinetics. Therapeutic drug monitoring is essential and conventionally has been guided by trough levels (C0). Recent evidence indicates that a single blood concentration measurement 2 h after CyA administration (C2) is a more accurate predictor of drug exposure and clinical events than determination of C0. To date, limited prospective data are available with respect to risks and benefits of C2 monitoring in renal transplant recipients, and little experience exists with C2 monitoring in maintenance patients.

Methods. In 127 long-term renal allograft recipients, we determined C2 levels in addition to conventional C0 and observed clinical outcome over a period of 13.6 ± 3.1 months. To determine the precision of monitoring, we repeatedly determined C0 and C2 levels in 46 stable patients without dose change.

Results. Clinical outcome was excellent (patient survival 100%, graft survival 97%), with only two borderline rejections, although C2 levels (564 ± 186 ng/ml) were lower than recommended so far for maintenance patients. We found no significant differences in C2 levels between patients with rejection and CyA toxicity. Receiver operating characteristic (ROC) analysis showed no prediction for risk of rejection, toxicity or infection by C2 levels. Repeated determinations of both C0 and C2 levels in 46 patients revealed a high intra-patient variability. In these patients, the coefficient of variation for C2 was only marginally better compared with C0.

Conclusions. We conclude that in maintenance patients, C2 concentrations between 500 and 600 ng/ml are well tolerated and provide effective and safe rejection prophylaxis. Although mean C2 levels do not seem to be helpful in identifying patients at risk for rejection, they may be useful to detect over-immunosuppression and to improve long-term allograft survival further by reducing CyA nephrotoxicity.

Keywords: C2 monitoring; cyclosporin A; maintenance immunosuppression; pharmacokinetics; renal transplant



   Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The introduction of cyclosporin A (CyA) into clinical practice was a major advance for the efficacy of immunosuppression. However, its optimal use has been limited by the narrow therapeutic window that allows adequate calcineurin inhibition and T-cell immunosuppression with minimum risk of serious side effects [1] and characterizes CyA as a critical-dose drug. Although the highly variable pharmacokinetics were improved by the introduction of the current microemulsion formulation (Neoral) [2,3], therapeutic drug monitoring remains an indispensable tool for management of CyA therapy. So far, dose adjustments have been guided on the basis of CyA trough blood levels (C0) to maintain CyA concentration within the narrow therapeutic range. However, trough levels do not reflect adequately total drug exposure, estimated by the area under the concentration–time curve (AUC) [4], and correlate poorly with clinical events in patients after organ transplantation [4,5].

Pharmacokinetic studies have shown that the AUC is a more sensitive predictor of acute and chronic rejection, graft survival rate and nephrotoxicity [6]. However, conventional methods of measuring AUC [7] require multiple samples and are therefore impractical in routine patient care. Therefore, further studies focused on limited sample strategies. The CyA whole blood concentration 2 h after dosing (C2) has been shown repeatedly to be the best single-point predictor of AUC0–4 h [8]. Prospective multicentre studies showed C2 to have close correlation with clinical outcome in the early post-transplant period and to serve as a reliable predictor of rejection risk [9,10].

Clinical studies [9,11] have focused on CyA absorption profiling using C2 monitoring during the first months after transplantation. Concerning C2 measurements as a monitoring tool in stable renal allograft recipients beyond the first 3 months after transplantation, only limited data are available [12,13]. It is essential to ensure that this method can be performed safely and effectively in an ambulatory patient population and to determine a therapeutic window for C2 levels in stable renal allograft recipients. This study therefore aimed to evaluate the feasability of C2 monitoring on an out-patient basis, to characterize CyA absorption profiles on the basis of C0 and C2 levels, and to determine the relationship between C2 levels and the risk of rejection in order to generate a therapeutic window for C2 values in long-term allograft recipients.



   Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this study, which was conducted between September 2000 and April 2002, we included all renal allograft recipients in our out-patient clinic who agreed to participate in the prospective investigation of C2 levels and clinical outcome. For eligibility, all patients had to be at least 3 months after transplantation and on stable immunosuppression with CyA (NeoralTM, Novartis Pharma, Basel, Switzerland). Patients with any disease that may affect absorption of CyA and any co-medication that may strongly interfere with CyA drug metabolism (e.g. diltiazem, erythromycin or St John's wort) were excluded from this study. CyA was administered at concentration-controlled doses based on whole-blood trough levels. The target range for CyA trough levels measured using a specific monoclonal-based immunoassay was 90–120 ng/ml. Measurement of C2 levels was additional and did not lead to dose adjustments.

Data from all renal allograft recipients with at least one available C2 concentration in addition to trough levels were analysed. One single measurement for each individual was analysed. For those patients with multiple measurements, the first available CyA level was used for analysis. The date of the measurement reflects the start of the prospective investigation. For C2 levels, a sampling time of 2 h ± 10 min after dosing was tolerated. For these routine measurements, patients were not fasted. At regular consecutive visits during follow-up, serum creatinine, blood pressure, concomitant medication and all clinically relevant events (rejection, CyA toxicity, infection and hospitalization) were documented prospectively in an electronic patient record system (‘TBase’). Acute allograft rejection was suspected by the presence of clinical signs, such as increased serum creatinine or decreased urine output; all rejection episodes were confirmed by core biopsy. Suspected CyA nephrotoxicity was defined on clinical grounds with decreasing renal function, elevated CyA levels and improvement of renal function after dose adjustment. Biopsy-proven toxicity was confirmed by histological signs of calcineurin inhibitor toxicity as described by Racusen et al. [14] with tubular vacuolization, segmental arteriolopathy, arteriolar myocyte vacuolization and striped or diffuse interstitial fibrosis. As infections, we documented all events with clinical and laboratory signs of viral or bacterial infections such as fever, in addition to an increase in C-reactive protein or change in white cell count, a positive urine culture or positive chest X-ray.

In a subgroup of 30 stable patients, a full 10-point pharmacokinetic measurement of CyA was performed. On the day of investigation, all patients were under steady-state conditions, medically stable and had fasted overnight. During the first 2 h after dosing, only water was allowed. Samples were drawn at 10 time points: 0, 30, 60 and 90 min, 2, 3, 4, 6, 8 and 12 h. The AUC was calculated using the trapezoidal rule for 10-point AUC and according to a standard formula for two-point AUC (AUC = 990 + 10.74 x C0 + 2.28 x C2) [15]. For the full 10-point AUC, we evaluated the Pearson correlation coefficient of single-time point samples with AUC(0–4) and AUC(0–12).

In order to determine precision of C2 monitoring, measurement of C0 and C2 was repeated during the next visit without dose change or change of co-medication in an additional subgroup of 46 renal allograft recipients. For the first two measurements, the Pearson correlation coefficient was calculated. The intra-patient coefficient of variation for further repeated determinations without dose change was calculated according to the following algorithm: standard deviation of CyA concentration, divided by the mean, converted to the percentage [(SD/mean) x 100].

CyA concentration was measured using a specific monoclonal antibody according to the manufacturer's guidelines (CEDIA assay, Microgenics Corporation, Fremont, CA). The centre participated in the international proficiency testing scheme for CyA measurements.

Statistical analysis
For each patient, we characterized CyA absorption, expressed as dose-adjusted C2 levels (C2/dose) and the ratio C2/C0. Mean and standard deviation of C0, C2, C2/dose, serum creatinine, serum cholesterol and blood pressure were calculated at the beginning and at the end of follow-up for all patients.

To evaluate the relationship between CyA levels and clinical events, we performed a receiver operating characteristic (ROC) curve analysis evaluating trough levels, C2 concentrations or absorption profile (C2/dose and C2/C0) as predictors of clinical events (rejection, toxicity and infection). This test is a suitable measure to summarize the discriminative power of a value and can range from 0.5 (no discrimination) to 1.0 (perfect discrimination) [16]. A value of 0.7–0.8 is considered to represent reasonable discrimination, and a value of >0.8 is good discrimination. When the ROC curve is plotted with 1 – specificity on the abscissa and the corresponding values for sensitivity on the ordinate, the point of the ROC curve closest to the upper left corner of the coordinate system (where sensitivity and specificity equal 1) represents the best cut-off value. Additionally, patients were divided into groups according to clinical events; differences between the groups were assessed by t-test and {chi}2 as appropriate.

All statistical analyses were performed using the Statistical Program of Social Sciences (SPSS 11.0 for Windows, SPSS Inc., Chicago, IL). All continuous data are expressed as mean ± SD.

Differences between groups were considered to be significant for a P-value of <0.05.



   Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In 127 long-term patients from our out-patient clinic, we determined 257 combined C0 and C2 levels and 30 full 10-point AUCs. The characteristics of the study population are shown in Table 1.


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Table 1. Demographic characteristics of 127 stable renal allograft recipients

 
All patients were on stable CyA medication bid (2.5 ± 0.8 mg/kg/day). As concomitant immunosuppression, 42% of patients received only mycophenolate mofetil (MMF), 26% only methylprednisolone; 12% had both MMF and methylprednisolone, and 12% only azathioprine in addition to CyA. In nine patients (7.1%), CyA was discontinued during follow-up due to nephrotoxicity, proven by renal allograft biopsy.

The mean C0 in all patients was 105 ± 33.8 ng/ml (range 15–186 ng/ml); mean C2 was 564 ± 186 ng/ml (104–1106 ng/ml). The distribution of C2 levels in the patient population is shown in Figure 1.



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Fig. 1. Distribution of C2 values in 127 stable renal allograft recipients.

 
As a consequence of the large variability in C2 levels, the calculated AUC had a similar degree of variability, ranging from 517 to 5049 ng/h/ml with a mean of 3400 ± 673 ng/h/ml.

To characterize CyA absorption of the individual patient, we calculated dose-adjusted C2 concentrations (C2/dose) as well as the ratio between C2 and trough concentrations (C2/C0). We observed a substantial inter-patient variation in CyA absorption in our patient population. Figure 2 shows a Gaussian distribution of absorption (C2/dose) with a range from 25 to 423 (ng/ml)/(mg/kg). The peak was between 200 and 250 (ng/ml)/(mg/kg) [mean = 225 ± 75 (ng/ml)/(mg/kg)]. For the ratio C2/C0 as a dose-independent measure of absorption, we obtained similar results: mean C2/C0 = 5.9 ± 2.3 with a range between 1.0 and 15.5.



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Fig. 2. Distribution of CyA absorption (C2/dose) in 127 stable allograft recipients.

 
Pharmacokinetic measurements
A full 10-point AUC0–12 was performed in a subgroup of 30 patients under standardized conditions. In this subgroup, comparable pharmacokinetic parameters were obtained. The results are summarized in Table 2 and Figure 3.


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Table 2. Mean ± SD of single time points and AUC in 30 full 12 h pharmacokinetic measurements

 


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Fig. 3. Ten-point AUC in 30 stable patients. All patients were under steady-state conditions and had fasted overnight. Samples were drawn pre-dose and at 30, 60 and 90 min, 2, 3, 4, 6, 8 and 12 h. The curve connects mean values of each time point.

 
From these studies, it became obvious that most pharmacokinetic variability occurs during the absorption phase. The peak concentration was reached after 1.2 ± 0.3 h with a Cmax of 769 ± 197 ng/ml. For those time points (C0, C2 and C3) that have been described previously to correspond well with total drug exposure [17,18], we calculated the Pearson correlation coefficient with AUC0–12 as well as AUC0–4. Results are shown in Table 3. There was a significant correlation of C0, C2 and C3 with AUC. Correlation with AUC0–12 did not differ between the single-time point samples. Trough levels correlated best with full AUC (r2 = 0.41); for C2 levels, there was a better correlation with AUC0–4 (r2 = 0.53), representing the absorption phase, than with full AUC (r2 = 0.46). C2 correlated better with AUC0–4 than C0 or C3 (r2 = 0.53 vs 0.26 or 0.29, respectively). Surprisingly, in our population, AUC0–4 correlated only poorly with AUC0–12 and calculated AUC.


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Table 3. Correlation (Pearson correlation coefficient r2) of single time point samples with AUC

 
Repeated measurements
In 46 patients, measurement of C0 and C2 levels was repeated after 35 ± 29 days without dose change. All patients were long-term transplant patients in steady state. Repeated determinations showed a poor correlation of C0 (r2 = 0.26). Interestingly, correlation of repeated C2 determinations gave better results (r2 = 0.59). Only a weak correlation (r2 = 0.16) was found concerning repeated CyA absorption, described as the ratio C2/C0, due to a considerable intra-patient variability.

Coefficient of variation in 34 patients for more than two repeated measurements without dose change was 17.2% (C0), 15.3% (C2) and 23.0% (C2/C0).

Clinical outcome
All 127 patients were followed regularly in our out-patient clinic over a period of at least 6 months (13.6 ± 3.1 months, range 6.4–19.2 months). Patient survival after 13.6 ± 3.1 months follow-up was 100%, graft survival 97.5%. Three allografts were lost due to chronic allograft dysfunction. Only two acute rejections (one borderline, one Type Ia according to Banff classification) were noted (at the time of CyA measurement and 7 months after CyA measurement, respectively); both responded well to treatment with steroids. Twenty-one patients (16.5%) had episodes of CyA toxicity (9 ± 7 months after CyA measurement); nine were proven by biopsy. Immunosuppression with CyA was discontinued in these nine patients due to biopsy-proven CyA nephrotoxicity. Viral and/or bacterial infections were noted in 58 cases (5.8 ± 4.6 months after CyA measurement); only one of them required admission to hospital. The patients were maintained on similar C0 target levels during follow-up; there was no difference between C0 at the time of the first measurement and at the time of clinical events (paired t-test). No significant change was observed during follow-up of the 127 patients with regard to renal function, blood pressure and routine laboratory data. However, serum creatinine increased slightly over the observation period (1.68–1.89 mg/dl). For the three patients with graft loss, we assigned the creatinine value at the day dialysis was initiated. For the patients who stopped CyA, we assigned the creatinine values at the time of change in medication. Mean values for serum creatinine, urea, serum cholesterol and blood pressure at the beginning and after 13 months follow-up are depicted in Table 4.


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Table 4. Important laboratory values of 127 patients at the beginning and end of follow-up (13.6 ± 3.1 months)

 
The value of C0, C2 or CyA absorption as a predictor of subsequent infection was assessed by ROC analysis. Due to the small numbers of rejections and CyA toxicity, no ROC analysis was performed for those events; for the event of infection (n = 58), we calculated the area under the ROC curve for C0, C2, C2/C0 and C2/dose. As an example, the ROC curve for C2 is shown in Figure 4. According to the ROC curve (area under the ROC curve for C0 = 0.560, C2 = 0.549, C2/C0 = 0.523, C2/dose = 0.568), no discriminative power could be detected for any of the parameters tested with regard to the event of an infection.



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Fig. 4. Receiver operating characteristic (ROC) curve showing C2 concentration as predictor of infection. For a given C2 value, the ordinate shows the corresponding true-positive rate and the abscissa shows the corresponding false-positive rate. As the area under the ROC curve was 0.549, no cut-off value was calculated.

 
Patients were divided into groups according to the clinical events. Mean and standard deviation were calculated for C0, C2, CyA absorption, AUC and CyA dose in each subgroup. CyA levels, dose, absorption and AUC for the different groups are shown in Table 5.


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Table 5. Mean CyA levels and dose for groups with different clinical events

 
Comparison between the groups (ANOVA) did not reveal a statistically significant difference. The two patients with rejection had the lowest values. Controls and patients with infection had the highest values. There were no differences in the mean values between patients with infection and controls, whereas the nine patients with biopsy-proven nephrotoxicity had lower mean values.



   Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Optimization of immunosuppression is critical to improve long-term outcome in transplant patients. Decisive for the level of CyA immunosuppression is the amount of systemic drug exposure. C2 has emerged as the best single-point sample on which to base CyA dosing, but there are limited data on target ranges and clinical benefit in long-term transplant patients. Here we report the results of a clinical study in 127 stable renal allograft recipients. In addition to conventional trough levels, we determined C2 levels and followed all patients with regard to clinical events and renal function. Despite low exposure, we observed excellent long-term results: only two acute rejections (one borderline, one Banff Ia) occurred during follow-up. The infections observed were very mild; only one required admission to hospital. Although exposure was lower in patients with rejections, we could not separate those patients from patients with infection or CyA nephrotoxicity, probably due to the low number of rejections.

C2 target levels have been proposed for the first months post-transplant in adult renal transplant patients receiving NeoralTM [19] with subsequent step-wise reductions in C2 target levels over time comparable with C0-based dose adjustments. However, recommended target levels for C2 are based on studies performed in North America; it is well known that, regarding trough levels, European guidelines propose lower concentrations than those aimed for in North America. Therefore, target C2 levels have to be adjusted to the European setting. This is the first European study assessing C2 monitoring in maintenance renal allograft recipients. It is important to note that CyA dose in our observational study was adjusted according to trough levels; they were targeted to a level of ~100 ng/ml. Measurement of C2 was additional and did not lead to dose adjustments. The mean AUC (3400 ng/ml/h) and corresponding C2 (500–600 ng/ml) levels were lower than those recommended before for long-term transplant patients [19]. The effect of adopting C2 monitoring in maintenance renal patients previously managed by C0 monitoring has been investigated by Cole et al. in a prospective single-centre trial, which showed that a high proportion (>40%) of maintenance patients have C2 levels exceeding pre-defined targets (>800 ng/ml) [13]. After dose reduction in those patients, a significant improvement in serum creatinine and blood pressure was observed. No episodes of acute rejection occurred in any of the patients in whom CyA dose was reduced. Dose reduction resulted in C2 levels of 600–700 ng/ml which are only slightly higher than C2 levels in this study.

Assessment of the influence of CyA levels or CyA absorption on clinical events after renal transplantation has been performed mainly in the initial phase after transplantation [9,10]. A retrospective study of 65 maintenance renal transplant patients (mean time post-transplant 55 months) proposed that there is an association between C2 levels and the risk of chronic allograft nephropathy [12]. At the time of assessment, 20 patients showed signs of chronic allograft dysfunction (CAD); they had significantly lower C2 levels than those without CAD. However, retrospective studies carry the risk of selection bias and may be confounded by several other factors. Considering the experience with our patients, it is conceivable that patients with poor graft function did not tolerate higher CyA levels. As a consequence, the optimal long-term target to minimize the risk of CAD needs to be established in a prospective study.

Similar to the study conducted by Cole et al. [13], we found a low incidence (<2%) of acute rejection episodes in maintenance patients. This may be due, in part, to the fact that the majority of our patients received MMF as adjunct therapy. When comparing the patient groups with rejection, CyA toxicity or infection, we observed a trend towards lower C0 and C2 levels as well as absorption in the rejection group. There are hardly any differences in the mean values between patients with infections and controls, whereas, in the case of biopsy-proven nephrotoxicity, there is a trend towards lower mean values. This could be due to the fact that these patients were already on a lower CyA dose due to clinical signs of nephrotoxicity at the outset of this study. However, due to low numbers, there was no statistically significant difference between the groups. Using a ROC curve analysis, no cut-off value for the prediction of any clinical event could be detected.

From our observations, we cannot define a lower limit for target C2 levels but we conclude that C2 levels of 600 ng/ml are sufficient to provide effective rejection prophylaxis. Further prospective studies using C2 as management tool have to be conducted in order to define a clear-cut therapeutic window. However, it is important to note that our favourable results were achieved with conventional C0 monitoring. It should be noted that clinical events occurred during the 13 months of follow-up and not necessarily at the time of CyA measurement (mean 5.7 ± 5.4 months later); however, our stable patients were maintained on the same target CyA levels during follow-up. There was no difference between C0 levels at the time of the first measurement and the time of the clinical event. Regarding the fact that we could not detect significant differences in C2 levels between the groups with rejection, CyA toxicity and infection and that we could not define a cut-off value to predict an increased risk for any of these events, C2 levels do not seem to be more helpful in identifying potential risks in long-term transplant patients than C0 levels. Nevertheless, they may help to identify high absorbers. In those patients, the determination of C2 levels may identify over-immunosuppression and enable the CyA dose to be lowered despite C0 within or even below the target range, still providing sufficient rejection prophylaxis.

In the 30 stable renal allograft recipients with a full AUC, we found a reasonable correlation between trough levels and measured full 12 h AUC. Surprisingly, C2 or C3 levels were not superior. This is in contrast to Perner et al. [15] who found an extremely poor correlation between trough levels and AUC in the initial phase after transplantation but a better correlation with C2 levels. In our patients, C2 correlated better with AUC0–4 than with AUC0–12 but exhibited no strong correlation with total AUC, either. In contrast to other studies [18], the correlation of C3 with AUC0–12 was not superior to that of C2. From these observations, we conclude that the correlation of C0 with AUC is sufficient to guide therapy in patients on maintenance therapy; this conclusion is supported by the clinical outcome in our observational study.

To determine the precision of C2 monitoring, we repeatedly measured C0, C2 and absorption in a subgroup of patients. So far, no data have been published on this clinically important topic. Repeated determinations of both C0 and C2 levels in 46 patients showed a high intra-patient variability. For trough levels, it has been described previously that a high intra-individual variability of CyA trough concentrations is associated with an increased incidence of acute and chronic rejection episodes, reduced 5-year graft survival and increased serum creatinine [20]. For C2 concentrations, the degree of variability and its influence on clinical outcome has not been investigated before. We observed a better but certainly not good correlation for C2 than for C0 in two repeated measurements without dose change. However, for multiple measurements without dose change, this effect was reduced (17 vs 15%); in those patients, there was only a marginally better coefficient of variation for C2 than for C0, reflecting variable CyA pharmacokinetics in the individual. This suggests that drug monitoring using C2 levels in transplant patients provides only a slightly more accurate and reliable measure of drug exposure in the individual patient. CyA absorption, described as the ratio C2/C0, showed only a weak correlation during repeated measurements, suggesting day-to-day variability of absorption. As there was no change in CyA dose between repeated measurements, the high variability does not seem to be due to dose-dependent saturation of transporters. However, it should be noted that for routine measurements of C0 and C2, in contrast to the 12 h profiles, patients were not fasted.

As described previously by David et al. [17], we observed profound inter-individual differences in the absorption of CyA, shown as the ratio C2/C0 as well as dose-adjusted C2 (C2/dose). The absorption phase is critical for T-cell inhibition by CyA. The degree of T-cell inhibition depends on the concentration of CyA available to enter T cells. Changes in drug concentration produce immediate and rapid changes in T-cell inhibition, with the maximal degree of inhibition correlating closely with C2. There is a wide variability in absorption profiles among the patients which reflects the variable pharmacokinetics of CyA; this may be due to episodic absorptive variations caused by co-administered over-the-counter medications and/or a variety of foods in the diet. Differences in absorption profiles play a key role in meeting the challenge of avoiding overexposure which places the patient at risk of nephrotoxicity and infection, but providing the minimum exposure required to prevent rejection.

We conclude that C0 concentrations of 100 ng/ml and C2 concentrations between 500 and 600 ng/ml are safe to provide effective rejection prophylaxis in stable transplant patients on dual or triple immunosuppression. Prediction of CyA exposure and precision was comparable for C0 and C2. C2 monitoring was not superior compared with conventional trough level monitoring regarding the prevention of infection and CyA toxicity. Although in our investigation neither C0 nor C2 levels seemed to be associated with clinical events, C2 levels seem to better reflect inter-individual absorption differences. They may help to identify those patients at risk of over-immunosuppression due to good CyA absorption and may enable the CyA dose to be lowered in those individuals. Based on the potential target range for C2 levels that has been identified in this investigation, a prospective randomized study comparing the efficacy of C0 vs C2 monitoring in maintenance patients could be initiated.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received for publication: 2. 4.04
Accepted in revised form: 4. 7.04