Limitations of C2 monitoring in renal transplant recipients

Gunilla Einecke1, Manuela Schütz1, Ingrid Mai2, Lutz Fritsche1, Markus Giessing3, Petra Glander1, Hans-H. Neumayer1 and Klemens Budde1

1 Department of Nephrology, 2 Institute for Clinical Pharmacology and 3 Department of Urology, Charité, Berlin, Germany

Correspondence and offprint requests to: Gunilla Einecke, Division of Nephrology and Transplant Immunology, 250 Heritage Medical Research Centre, University of Alberta, Edmonton T6G 2S2, Canada. Email: gunilla.einecke{at}ualberta.ca



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Background. Recent developments have proposed the cyclosporin (CsA) concentration at 2 h post-dose (C2) as the best single time-point predictor of the extent of CsA exposure and as the optimal basis for monitoring immunosuppressive therapy in renal transplant patients. The present study sought to validate the cornerstones of the current concept of C2 monitoring.

Methods. We assessed the predictive value, dose proportionality and intrapatient variability of C2 levels in 41 de novo renal transplant recipients treated with CsA microemulsion, steroids, mycophenolate sodium and basiliximab.

Results. Patients with rejection and patients with CsA nephrotoxicity had lower C2 (P = NS) and absorption (P<0.05 for toxicity), while C0 did not show any significant difference. Receiver operating characteristic analysis did not detect discriminative C2 values as a predictor of rejection or toxicity. In a substantial number of patients (29%) we observed poor and/or slow absorption, with C0 >300 ng/ml and C2 levels <800 ng/ml during the first month and a high rate of complications in these patients (18% rejection, 64% toxicity). Absorption increased over the first month post-transplant. Analysis of dose changes indicated that C2 levels are not dose-proportional. Intrapatient variability of C2 was as high as that of C0.

Conclusions. C2 levels do not predict rejection or toxicity. C2 monitoring alone does not detect toxicity in poor and/or slow absorbers, who constitute a significant proportion of patients. Changes in absorption over time, high intrapatient variability and lack of dose proportionality constitute further limitations of the C2 monitoring concept in the early post-transplant phase.

Keywords: C2 monitoring; cyclosporin; immunosuppression; pharmacokinetics; renal transplant patients



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
For >20 years, cyclosporin (CsA) has been the mainstay of most immunosuppressive protocols. Although the highly variable pharmacokinetics was improved by the introduction of the current CsA formulation (Neoral®), its optimal use is limited by a low therapeutic index that requires individualized monitoring of blood concentration. Mounting evidence shows that conventional monitoring by measurement of pre-dose blood concentrations (C0) is not sufficient due to a poor correlation with drug exposure, estimated by area under the curve (AUC), or clinical events [1].

Recent developments have proposed a monitoring strategy based on the CsA concentration at 2 h post-dose (C2) as the optimal single time-point predictor of AUC0–4 h and the extent of CsA exposure [2]. Some clinical data indicate that higher C2 levels are correlated with a lower risk of acute rejection during the early post-transplant period in patients receiving Neoral® [3,4]. A recently published study in maintenance renal transplant patients showed that dose reduction in patients with C2 levels above target leads to improvement in renal function and blood pressure [5]. Results available to date [6,7] suggest that the overall safety profile of Neoral® in de novo renal transplant recipients managed by C2 monitoring is at least equivalent to that with C0 monitoring. However, no controlled clinical trials with long-term follow-up have confirmed the long-term safety and efficacy of Neoral® C2 monitoring. In the recent recommendations for the use of C2 monitoring in clinical practice [8] the authors propose that the monitoring of C2 is an accurate method of estimating the extent of CsA absorption and exposure in the individual and that dose changes lead to proportional changes in C2 levels. The present study sought to validate the cornerstones of the current concept of C2 monitoring by assessing the predictive value, the dose proportionality and the intrapatient variability of C2 levels in de novo renal transplant recipients.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Between February 2002 and April 2003, our centre participated in an international multicentre trial to assess the safety and the efficacy of a combination therapy consisting of enteric-coated mycophenolic acid (EC-MPS; Novartis Pharma, Basel, Switzerland), basiliximab (Simulect®; Novartis Pharma), steroids and cyclosporin (Neoral®; Novartis Pharma) in de novo kidney transplant recipients. We enrolled all patients who fulfilled the inclusion and exclusion criteria (inclusion criteria: age 18–75 years and recipient of a kidney transplant; exclusion criteria: ABO incompatibility, PRA>50%, liver disease, any other immunosuppressive therapy within the last 4 weeks, any malignancies other than basalioma, pregnancy and drug or alcohol abuse). Patients were enrolled after transplantation and before the first administration of the study medication. We enrolled 41 patients in this trial. All of these patients gave informed consent to participate in the additional prospective investigation of CsA levels and clinical outcome over a period of 6 months post-transplantation that is presented here.

Patients were treated with EC-MPS (720 mg b.i.d.) in combination with standard doses of Simulect® (20 mg pre-operatively and on day 4), steroids and full-dose Neoral®, adjusted by C2 monitoring to a target level of 1500 ng/ml, for 4 weeks. Steroids were given as an initial bolus of 500 mg intravenous and tapered thereafter according to standard protocol (40 mg at day 7, 20 mg after month 1, 8 mg after month 3 and 4 mg after month 6). After 4 weeks, patients were randomized into two groups. In the first group, normal Neoral® doses were applied with C2 target levels of 1500 ng/ml during months 2 and 3 and 1150 ng/ml during months 4–6. Patients from the second group received a reduced dose of Neoral® with target levels of 1150 ng/ml during months 2 and 3 and 750 ng/ml during months 4–6. For C2 levels a sampling time of 2 h±10 min after dosing was tolerated. For these routine measurements, patients were not fasted. Measurement of trough levels was additional and was not required for dose adjustments. Only those CsA levels that were measured in steady state (≥36 h after dose change) were included in the analysis. None of the patients received co-medication that may interfere with CsA drug metabolism.

Patients were followed in our outpatient clinic. At regular consecutive visits, serum creatinine, concomitant medication and all clinically relevant events (rejection or CsA toxicity) were documented prospectively in an electronic patient record database (TBase®; German Transplantation Society, Regensburg, Germany). 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 unless clinically contraindicated. Clinically suspected CsA nephrotoxicity was defined as worsening renal function that resolved after CsA dose reduction. Biopsy-proven nephrotoxicity was confirmed by histological signs of calcineurin-inhibitor toxicity, such as tubular vacuolization, segmental arteriolopathy, arteriolar myocyte vacuolization and striped or diffuse interstitial fibrosis. We defined delayed graft function as the need for dialysis within the first week after transplantation. Liver toxicity was diagnosed on the basis of elevated liver enzymes (GOT three times above the normal range) in the presence of elevated CsA levels and improvement of liver function after reduction of CsA dose.

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



   Data analysis
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
For each patient, we characterized relative CsA absorption, expressed as dose-adjusted C2 levels (C2/dose). C2 levels have been shown to closely correlate with both the full 12 h AUC and the absorption phase (AUC0–4 h); this assessment of relative absorption can be obtained with routine CsA measurements and does not require additional pharmacokinetic studies and allows comparison to other pharmacokinetic studies with stratification of patients into low and high absorbers [4]. The means±SD of C0 and C2 concentrations and CsA absorption were calculated for all patients. Because patients were randomized to different target levels after the first month, we did not analyse drug concentrations after this period.

To analyse intrapatient variability for repeated measurements without dose change, we calculated the coefficient of variation (CV) as the SD of the analysed parameter, divided by the mean, and converted to a percentage [(SD/mean) x 100]. To test for dose proportionality, the ratios of old and new dose and old and new drug level or absorption were calculated. After testing for normality (Kolmogorov–Smirnov test), parameters were compared by linear regression analysis and the Pearson or Spearman correlation coefficient, as appropriate.

To evaluate the relationship between CsA levels or CsA absorption and clinical events, we performed a receiver operating characteristic (ROC) curve analysis evaluating trough levels, C2 concentrations or absorption profile (C2/dose) as predictors of clinical events (rejection or toxicity). Additionally, patients were divided into groups according to clinical events; differences between the groups were assessed by t-test and chi-square, as appropriate. Percentages were calculated based on the patients for whom C2 levels were available during the particular period.

All statistical analyses were performed using the Statistical Program of Social Sciences (SPSS 11.0 for Windows®; SPSS Inc., Chicago, IL, USA). All continuous data are expressed as means±SD. Differences between groups were considered to be significant for a P-value of <0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Patients and clinical outcome
In 41 renal transplant patients we determined 366 C2 and corresponding C0 levels in steady-state conditions. Demographics and baseline characteristics of the patients are shown in Table 1. Three patients discontinued treatment with CsA within the first 6 months; they were switched to tacrolimus due to severe rejection within the first week post-transplant. At 6 months post-transplantation, patient and graft survival were 100%. Acute rejection was suspected in eight patients (19.5%) and in six cases proven by biopsy. Median time to rejection was 11 days; 6/8 (75%) of the rejections were observed during the first month. Of the 38 patients that remained on therapy with CsA, 10 (26%) showed signs of CsA nephrotoxicity; in five cases this was proven by biopsy. Liver toxicity was noted in 19/38 patients (50%). Twenty-two patients (58%) experienced either liver or nephrotoxicity. Steady-state mean pharmacokinetic parameters during the first month are shown in Table 2; mean CsA starting dose was 8.5±2.0 mg/kg/day.


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Table 1. Patient demographics and baseline characteristics in 41 de novo renal transplant patients

 

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Table 2. Mean pharmacokinetic parameters in 41 de novo renal transplant patients during the first month post-transplant

 
C2 levels as a predictor of under- and overdosing
To assess the predictive value of C2 levels, we stratified patients into groups according to C2 level and absorption. Target levels for C2 >1500 ng/ml were reached by 3/40 (8%) of the patients during week 1 and by 13/36 (36%) during week 2. Rejection rates during the first month in those patients were 0% vs 20% and 0% vs 18%, respectively. Incidence of liver toxicity during the first month in patients with C2 above target level in week 1 was 66% vs 33% and in those above target level in the second week 38% vs 39%; nephrotoxicity occurred in 29% vs 0% and 24% vs 31%. Target levels of >1200 ng/ml were reached by 8/40 patients (20%) during week 1 and by 25/36 (69%) during week 2. Rejection rates during the first month in these patients were 0% vs 16% and 0% vs 18%, respectively. The incidence of liver toxicity during the first month in patients with C2 above target was 25% vs 38% (week 1) and 32% vs 55% (week 2); nephrotoxicity during the first month occurred in 13% vs 30% (week 1) and 28% vs 27% (week 2). We were unable to demonstrate significant associations with C2 levels above or below the target for any of these events during the first month post-transplant.

A subgroup of 11/38 patients (29%) had low C2 levels (<800 ng/ml) with corresponding high trough levels (>300 ng/ml), suggesting poor and/or slow absorption, at least at one time point after transplantation; in all cases, this was observed during the first month post-transplant. Of these 11 patients, seven (64%) showed signs of either liver or nephrotoxicity (nephrotoxicity: n = 4, 36%; liver toxicity: n = 6, 55%) and two patients (18%) had a rejection during the first month, compared with 12/27 (44%) liver or nephrotoxicity (nephrotoxicity: n = 6, 22%; liver toxicity: n = 10, 33%) and 2/27 (7.4%) rejection in the other patients during the same time period post-transplant.

When comparing pharmacokinetic parameters between the group of patients experiencing acute rejection during the first month (n = 6) and those remaining rejection-free during this period (n = 35), trough levels at the time of diagnosis did not show significant difference compared with the mean levels during the first month in the other patients (210 vs 244 ng/ml; P = NS); C2 concentrations and C2/dose were lower in the patients with rejection [C2: 740 vs 1095 ng/ml; C2/dose: 128 vs 170 (ng/ml)/(mg/kg)], although this did not reach statistical significance. A corresponding observation was made in patients with nephrotoxicity (n = 10) and in those with liver toxicity (n = 14) during the first month, where C0 levels in the last 10 days before diagnosis were not different (nephrotoxicity: 237 vs 255 ng/ml; liver toxicity: 232 vs 251 ng/ml), while mean C2 levels and absorption were lower (C2: nephrotoxicity: 1027 vs 1095 ng/ml, P = NS; liver toxicity: 907 vs 1120 ng/ml, P = NS; C2/dose: nephrotoxicity: 121 vs 168 (ng/ml)/(mg/kg), P<0.05; liver toxicity: 108 vs 164 (ng/ml)/(mg/kg), P<0.01) compared with the mean pharmacokinetic levels during the first month post-transplant in the patients without toxicity (Figure 1). ROC analysis evaluating C0, C2 or CsA absorption as predictor of rejection or CsA toxicity showed only a small area under the curve; therefore, no discriminative values could be calculated in relation to any of the clinical events. As an example, the ROC curve for nephrotoxicity is shown in Figure 2.



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Fig. 1. Key pharmacokinetic parameters for patients with rejection, CsA nephrotoxicity and liver toxicity during the first month post-transplant. *P<0.05, **P<0.01.

 


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Fig. 2. ROC analysis for C2 levels as predictor of nephrotoxicity. AUC was 0.43; therefore, no discriminative value for C2 levels could be determined.

 
Because both patients with rejection and patients with CsA toxicity had lower CsA absorption and a tendency to lower C2 levels, we further analysed the relationship between renal function and CsA exposure. At days 7 or 14 there was no significant difference in trough levels; in contrast, linear regression analysis showed a weak but significant (P<0.001) negative correlation (r2 = 0.15) between the creatinine at day 7 and mean CsA absorption as well as between the creatinine at 1 month and C2 concentration during weeks 2–4 (r2 = 0.125, P = 0.02), indicating that patients with lower serum creatinine tend to have higher C2 values. However, residual values were substantial and only a small percentage of the variation in creatinine (15%) could be attributed to differences in absorption or drug concentrations.

Changes in CsA absorption over time
CsA absorption, as detected by C2 levels, was poor in the first post-operative days and improved significantly (P<0.05) over the first month (Table 2). Despite dose adjustments, target C2 levels were not reached until week 2 in the majority of our patients. By the end of the first week, only 20% of patients reached C2 concentrations >1200 mg/dl and only three patients had levels >1500 ng/ml despite an increase in CsA dose. Corresponding mean trough levels were 200–300 ng/ml. During the second post-operative week, absorption improved significantly (P = 0.001): by day 14 the majority of patients had reached a level of ≥1200 ng/ml and 36% showed levels >1500 ng/ml, despite a decrease in CsA dose to 6.5 mg/kg/day. The changes in CsA absorption and corresponding dose adjustments to reach target levels are illustrated in Figure 3.



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Fig. 3. Key pharmacokinetic parameters in 41 patients in the post-transplant period. (A) CsA absorption increased over time but showed high inter- and intrapatient variability. (B) CsA dose increased in the initial post-operative period to reach target levels and decreased over time.

 
C2 levels are not dose-proportional
Analysis of the relationship between dose adjustments (ratio of previous and new CsA dose, expressed as {Delta}dose) and corresponding changes in C2 levels (ratio of previous and new C2 concentration in steady state, {Delta}C2) showed only moderate correlation (Table 3). Figure 4 shows the correlation for changes in CsA concentration with dose adjustments during the first 6 months post-transplant and illustrates the wide variation from the expected values. Regression analysis using {Delta}C2 or {Delta}C0 as dependent and {Delta}dose as independent parameter confirmed a linear but very weak relationship between dose changes and drug concentrations. However, the coefficient of determination was very small (r2 = 0.13 for C0; r2 = 0.09 for C2), indicating that only a small percentage of the variance in CsA levels is explained by dose changes. At any given time-point, there was no good correlation between CsA levels and CsA dose (C0: days 1–15: r = 0.07; days 16–30: r = 0.24. C2: days 1–15: r = 0.17; days 16–30: r = 0.50). Multiple repeated measurements without dose changes showed that although CsA absorption improved and stabilized over time, a considerable inter- and intrapatient variability remained; the CV was similar for C0 and C2 levels during follow-up (Table 4).


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Table 3. Correlation coefficients (r) between doze change and the observed change in CsA levels for patients with dose changes during different time periods after transplantation.

 


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Fig. 4. Correlation between dose changes and changes in CsA concentration in 41 de novo renal transplant patients during the first 6 months post-transplant revealed only moderate correlation for both C0 (A) and C2 (B), with a wide variation in observed values.

 

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Table 4. Coefficient of variation (CV) for repeated measurements in steady state during different time periods after transplantation for patients without dose changes.

 


   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 
Despite lower than recommended C2 levels [9] we had good clinical outcome: patient and graft survival were 100% after 6 months' follow-up, with a rejection rate of 19%. On the basis of C2 levels or absorption, we were not able to separate patients with acute rejection from patients with toxicity. Most importantly, many patients showed signs of CsA toxicity despite low C2 levels, reflecting an unusual absorption pattern that cannot be detected by C2 levels alone. Despite dose adjustments in order to reach the recommended target C2 levels, many of our patients did not reach the proposed levels until 2 weeks post-transplant, probably due to poor absorption in the initial post-operative period. Contrary to previous consensus statements [8], C2 levels showed poor dose proportionality. Only 15% of change in C2 levels could be attributed to dose changes, suggesting that other factors are more important for the observed initially poor CsA absorption which increases during the early post-transplant period, including the improvement of uraemia and changes related to P-glycoprotein and cytochrome P450–3A4. Interactions with CsA pharmacokinetics due to the use of mycophenolic acid seem unlikely, as previous studies have not shown any alterations in CsA pharmacokinetics by MPA [10]. Although C2 monitoring has improved our understanding of CsA absorption substantially, our study points towards some limitations of this concept.

Our results do not support the hypothesis that C2 monitoring as a management tool for immunosuppressive therapy is a good predictor for the risk of rejection or CsA toxicity and, subsequently, provide a substantial clinical benefit compared with the conventional measurement of trough levels. Although patients who experienced acute rejection showed lower C2 levels than the total patient population, we made the same observation in many patients with CsA nephrotoxicity. When patients were stratified into groups according to C2 level and absorption, no association between C2 levels and rejection or signs of liver or nephrotoxicity could be demonstrated. In a ROC analysis we could not detect any discriminative power for C2 levels regarding CsA toxicity or rejection. Previously, several uncontrolled trials have reported an association between C2 levels and clinical outcome [3,11]. In a prospective single-centre trial [7], the authors did not observe any significant difference in serum creatinine levels between patients managed by C2 or C0 monitoring. Although the results of a randomized, prospective, multicentre trial comparing AUC monitoring with trough monitoring in 204 patients [4] showed statistical associations between CsA exposure and rejection rates, this study failed to demonstrate any significant clinical benefit of AUC measurement with respect to rejection rate, rejection severity, serum creatinine, adverse events or CsA nephrotoxicity. Finally, a recent report of a retrospective analysis showed that in patients treated with basiliximab there is no correlation between C2 levels and clinical outcome [12]. Thus, our study prospectively verified the retrospective observation that, in combination with basiliximab, CsA exposure lower than previously recommended is sufficient for excellent rejection prophylaxis.

This is the first study analysing the trough levels in a large subgroup of patients, who had at least at one time point in the immediate post-transplant period low C2 levels (<800 ng/ml). These patients frequently have high corresponding trough levels (>300 ng/ml) (29% of our CsA-treated patients), suggesting poor and/or slow absorption. Previous studies did not further analyse patients with low C2 values [5,6]. Despite having C2 levels far below the target range, this group of patients did not show higher rejection rates. On the contrary, in 64% of these patients we observed signs of CsA toxicity, indicating a CsA overexposure that cannot be detected by C2 monitoring alone. Our results imply that low C2 levels do not in all cases represent an increased risk of rejection. In addition, C2 monitoring alone does not detect overexposure in all patients. Further evaluation of the absorption profile may be necessary to distinguish true low absorbers, who would benefit from an increase in CsA dose, from slow absorbers, who may be at risk for toxicity. Repeated dose adjustments in patients with low C2 levels in order to reach the proposed target C2 level may lead to a dangerous overexposure in this subgroup of patients. Other additional measurements, such as C6, may be necessary to further evaluate this critical subgroup of patients and to clarify the discrimination between low and slow absorbers. The determination of trough levels in addition to C2 levels can also help to estimate the exposure in the individual patient [13]. As a consequence of our observations with a high incidence of toxicity in patients with low C2 levels, we propose to avoid the adoption of C2 levels as a single monitoring tool. Further research on this subgroup of patients, who have a high risk for developing CsA-associated side effects, is needed in order to get a better insight into the absorption and metabolism of CsA in the early post-operative period.

High interindividual differences in CsA absorption, as seen in our patients, are well described. The majority of patients did not reach the proposed target levels during the first week post-transplant, despite adequate dose adjustments. These were performed according to the formula proposed by Cole et al. [8], unless the patient showed signs of CsA related toxicity. We observed poor CsA absorption during the first post-operative days, with significant improvement over the first 2 months. These findings show that despite high initial CsA doses it is difficult to reach the proposed C2 concentrations in the immediate post-transplant period and are consistent with those of other authors [14]. In a study by Mahalati et al. [11] in which intensive monitoring was used to reach a specific therapeutic window early after transplantation, only 60% of patients reached target levels on post-operative day 3; the required CsA doses were not quoted. While the increase in dose-adjusted CsA concentrations observed during the first week may be predominantly related to drug accumulation after multiple dose administration, the further increase observed between days 8 and 30 cannot be explained by this effect, since doses were reduced and measurements were done at steady state. These findings suggest that the increase in dose-adjusted CsA exposure observed after transplantation is related to a time-dependent increase in relative bioavailability of CsA [15]. In the initial post-transplant period, we observed a negative correlation between renal function and absorption, suggesting that uraemia might be one of the factors influencing CsA absorption. In an animal model it has been shown that rats with chronic renal failure absorb CsA poorly [16]. Patients on maintenance haemodialysis have lower CsA absorption than transplant patients [17]. In a prospective trial only 20% of patients with delayed graft function reached C2 target levels compared to 61% with immediate graft function [6]. Although in our study the correlation between renal function and CsA absorption was only weak, poor renal function may contribute to low and/or slow absorption with resulting low C2 levels; this possibility should be considered before increasing CsA dose in an attempt to reach target levels. However, the causal relationship between those two parameters remains to be determined. Other factors may also influence CsA absorption and contribute to the increase in bioavailability over time. After transplant surgery, absorption of orally delivered drugs is generally reduced, depending on the type and the duration of anaesthesia, hydration, reduced bile flow and intestinal motility. Although the microemulsion formulation has minimized the poor solubility and high lipophilicity of CsA, some of the above-mentioned factors may still have an impact on CsA absorption. Furthermore, differences in content and activity of cytochrome P450–3A4 and P-glycoprotein may change the absorption of CsA [18]. In rats, blood CsA concentrations increase following chronic daily administration and are paralleled by a decrease in hepatic P450 protein expression and microsomal metabolic activity, which suggests that time-dependent P450 suppression by CsA may contribute to the observed time-dependent changes in CsA pharmacokinetics [19].

Previous observations of a relationship between C2 levels and CsA dose have led to the hypothesis that it is possible to calculate the required dose change to reach a desired C2 level on the basis of the previous dose and current CsA levels [8]. However, in our cohort only a moderate correlation (r = 0.5) between CsA dose and the corresponding changes in CsA levels was observed. This correlation was similarly poor for C2 and C0 levels and did not improve significantly over time. Linear regression analysis revealed that only a small percentage of variation in C2 levels can be explained by dose changes, indicating that other factors have a higher impact on actual changes in C2 levels. Other equations to calculate dose adjustments have been suggested [20], but the authors encountered similar difficulties. The proposed equations were valid for only 50% of the recipients; about half the patients escaped the proposed formula and did not reach the expected CsA concentration. The large variability of CsA levels, even in repeated measurements without dose change (CV of 20% for both C2 and C0), contributes to the difficulties in predicting C2 levels.

In summary, in the initial post-operative period, many patients did not reach the desired target levels despite dose adjustment; nevertheless, we observed an excellent clinical outcome. We conclude that, at least when using the combination of Neoral® with Simulect®, EC-MPS (Myfortic®) and steroids, lower C2 levels than recommended previously are sufficient for good rejection prophylaxis. The level of immunosuppression, as detected by C2 monitoring, was not associated with the incidence of rejection or CsA toxicity in our patient cohort. A subgroup of patients with low C2 and high corresponding trough levels had a high incidence of CsA toxicity, but did not show an increased rejection rate. Although C2 monitoring may reveal otherwise undetected overexposure to CsA and may help to lower the dose in such patients, it may be dangerous to apply isolated C2 monitoring to all patients regardless of their true exposure and absorption profile. The proposed dose proportionality of C2 levels could not be confirmed in our patient population, rendering decision about dose changes to reach target levels difficult, especially as CsA absorption increases in the early post-operative period. C2 monitoring may help to better estimate the CsA exposure in individual patients; however, our study points towards some limitation of the current concept of C2 monitoring and further trials are warranted before its widespread adoption.



   Acknowledgments
 
The study was funded by a grant from Novartis Pharmaceuticals, Germany.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Data analysis
 Results
 Discussion
 References
 

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Received for publication: 8. 4.04
Accepted in revised form: 11. 3.05





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