How should microemulsified Cyclosporine A (Neoral®) therapy in patients with nephrotic syndrome be monitored?

Guido Filler

Department of Pediatrics, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada

Correspondence and offprint requests to: Guido Filler, Division of Nephrology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada. Email: filler{at}cheo.on.ca

Keywords: Cyclosporine A; Sandimmune Neoral; Nephrotic syndrome; Steroid-resistant nephrotic syndrome; Pharmacokinetics



   Introduction
 Top
 Introduction
 Pharmacokinetics of CyA ME...
 Uncertainty about the target...
 Conclusions
 References
 
Cyclosporine A (CyA) has been used empirically for almost two decades in the treatment of severe forms of idiopathic nephrotic syndrome (NS), in both children and adults [1]. The mechanism of CyA's action remains unclear. It may be related to immunosuppressive or haemodynamic properties, or have an effect on heparan sulfate, the main component of the glomerular charge barrier [2]. Initially, the therapy was performed with ‘classic’ Cyclosporine (Sandimmune®). Because of substantial inter- and intra-patient variability and a narrow therapeutic window, therapeutic drug monitoring of Cyclosporine therapy is mandatory [3,4]. With ‘classic’ CyA, trough level monitoring was recommended.

In the mid-1990s a microemulsified (ME) formulation of Cyclosporine (Neoral®) became available and many patients were converted because of more predictable pharmacokinetics—not always without problems [5]. Similar to renal transplant patients, patients with NS were often converted from the classic Cyclosporine to the microemulsified formulation (CyA ME). There is growing evidence that CyA ME should be monitored using the 2 h post-intake concentration (C2) rather than the pre- or post-dose trough level. This has been studied extensively in patients receiving a solid organ transplant, both in adults [6] and in children [7]. Targeting of C2 concentration as part of a post-transplantation treatment strategy is leading to excellent outcomes in adult transplantation with the ME Cyclosporine [8]. As CyA ME is used increasingly in patients with NS, the question arises whether C2 monitoring is also beneficial in patients with NS. However, even recent studies have not addressed this question in detail [9].



   Pharmacokinetics of CyA ME in patients with NS
 Top
 Introduction
 Pharmacokinetics of CyA ME...
 Uncertainty about the target...
 Conclusions
 References
 
Few studies have evaluated the pharmacokinetics of CyA [10] or CyA ME in children [11,12] and they are limited to small numbers. However, the pharmacokinetics appear to be similar to solid organ transplant recipients with higher maximum concentrations and an earlier maximum concentration when compared to the classic CyA [10].

Over a 10-year period, both in Berlin and in Ottawa, we have accumulated 34 pharmacokinetic (PK) profiles from 32 paediatric patients with NS on conventional CyA and 49 complete PK profiles on 32 similar patients who were treated with CyA ME. The PK profiles are shown in Figure 1. The PK monitoring has been described elsewhere in detail [13].



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Fig. 1. Complete 10-point PK profiles from children with steroid-sensitive and steroid-resistant NS. Thirty-four PK profiles were obtained on the classic CyA, and 42 PK profiles were obtained on CyA ME.

 
In the classic Cyclosporine group (11.7±4.4 years of age; six female patients; mean weight 45.2±18.2 kg; mean height 150.7±22.8 cm), the mean morning trough level was 139.3±44.72 ng/ml, not significantly different from the 12 h post-dose trough level of 110.7±34.62 ng/ml. The mean dose was 5.77±2.38 mg/kg or 173±51 mg/m2/day. The mean area under the curve (AUC) was 2950±933 ng x h/ml. For all sampling points, there was a significant correlation between the concentration and the AUC. With conventional CyA, there was only a weak, but significant, correlation (r = 0.3475, P = 0.0441) between the trough level and the AUC. This was only slightly better for the post-dose trough level (r = 0.3826, P = 0.0255). The best correlation between the trough level and the AUC occurred for the 6 h post-dose concentration (C6, r = 0.7200, P<0.0001).

In the CyA ME group, mean age was 10.2±4.9 years, mean weight was 40.4±24.9 kg and mean height was 135.0±27.8 cm. The mean morning trough level was 114.4±37.7 ng/ml, not significantly different from the post-dose trough level of 104.1± 37.2 ng/ml. The mean dose was 4.84±2.09 mg/kg or 156.5±39.4 mg/m2/day. The mean AUC was 3819±1378 n x h/ml. The dose normalized AUC was 25.21±8.20 ng x m2 x h/ml x mg, significantly higher than the dose normalized AUC of 18.66±8.68 ng x m2 x h/ml x mg obtained on the classic CyA (P = 0.0008, unpaired Student's t-test). In other words, the average dose normalized AUC on CyA ME was 35% higher when compared to the classic formulation. For CyA ME, there was a very significant (P<0.0001) positive correlation between the pre-dose trough concentration (C0), and at one (C1) and 2 h post-intake (C2), and the correlation coefficients were 0.6485 (C0), 0.5522 (C1) and 0.8292 (C2), respectively. The calculated regression lines and between AUC and C0, C1 and C2 levels in these patients with nephrotic syndrome read AUC(Cn) = (Cn – b)/m, where n is the hour after intake, m is the slope and b the constant, with m = 0.01775 and b = 46.64 for C0, m = 0.1945 and b = 74.96 for C1 and m = 0.1474 and b = 129.5 for C2. Bland and Altman analysis revealed the least bias (–4.14±24.84%, 95% confidence interval –52.8 to 44.6%) for the 2 h concentration. It is noteworthy that all of the formulae underestimate the actual AUC in the low range (Figure 2). These data suggest that the AUC can be calculated from the 2 h concentration using AUC(C2) = (C2 – 129.5)/0.1474. It remains to be established whether a 95% confidence interval with 50% over and underestimation is clinically acceptable. Meier-Kriesche et al. [14] suggested using C0, C2 and C4 after analyzing 45 complete PK profiles from 19 paediatric kidney transplant patients. They reported an r2 of 0.99 and a range of the prediction error from –36 to +17%. It is conceivable that an algorithm based on more-point sampling also yields better agreement in patients with nephrotic syndrome.



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Fig. 2. Bland and Altman analysis for agreement between actual AUC and AUC calculated from the 2 h concentration using linear regression analysis. There was reasonable agreement with an average bias of –4%; however, there was a significant skew towards underestimation of AUC in the low range.

 


   Uncertainty about the target AUC and target C2 concentrations
 Top
 Introduction
 Pharmacokinetics of CyA ME...
 Uncertainty about the target...
 Conclusions
 References
 
Similar to the situation in solid organ transplantation, there remains the uncertainty of the correct target AUC [12,15] and thus targets for C2. Some centres have established target C2 concentrations in renal transplantation [16,17]. Interestingly, the average AUC of ~3800 ng x h/ml in our group of patients with NS is similar to that of long-term renal transplant recipients [18]. It is unclear whether these targets can be applied in patients with NS. There is evidence that patients in remission require lower Cyclosporine levels when compared to patients with proteinuria [19]. In view of the substantial long-term CyA nephrotoxicity, even in patients with idiopathic NS [20], these target levels will have to be established.



   Conclusions
 Top
 Introduction
 Pharmacokinetics of CyA ME...
 Uncertainty about the target...
 Conclusions
 References
 
Similar to solid organ transplant recipients, patients with NS on Cyclosporine ME therapy show a better correlation between the 2 h post-dose CyA concentration and the AUC than with the trough level. The AUC can be predicted from the C2 concentration. Target C2 concentrations have not been established. The practicality of C2 monitoring may limit this approach. However, C2 monitoring or the determination of a full PK profile should be considered in case of suspected CyA nephrotoxicity.

Conflict of interest statement. The author received a grant from Novartis Canada Inc. over CDN $1500 for the submission of the chart review for the evaluation of the PK profiles to the institutional review board (IRB). This very amount is the current sum that the IRB charges for industry-sponsored studies. No additional funding was received. The author has no affiliation with Novartis in any form and owns no stocks.



   References
 Top
 Introduction
 Pharmacokinetics of CyA ME...
 Uncertainty about the target...
 Conclusions
 References
 

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