Neoral C2 monitoring in maintenance liver transplant patients: A step forward?

Therapeutic drug monitoring (TDM) is required for cyclosporine (CsA) use because of the drug's narrow therapeutic index.1, 2 It was initially believed that monitoring Cmin (C0) would be the most reproducible value accurately reflecting drug exposure, area under the time concentration curve (AUC), and the least likely to be affected by drug absorption and distribution phases.3, 4 While it is clear that AUC correlates well with freedom both from rejection and toxicity, C0 does not correlate well with either exposure or clinical events.5 The microemulsion formulation of CsA, Neoral, was developed to address some of the problems associated with the previous galenic formulation of CsA, Sandimmune.6 Data have shown that Neoral provides a closer correlation between dose and AUC and C0 with less inter- and intrapatient variability.7 However, the correlation between C0 and AUC, although markedly better for Neoral than for Sandimmune, has not proven to be sufficiently accurate to be used for clinical management.8 The molecular basis of the immunosuppressive effects of CsA has now been identified.9, 10 Once CsA enters the cell, it binds to a ubiquitous intracellular protein, cyclophilin. This binary complex is the active drug that engages calcineurin, a widely distributed calcium activated serine phosphatase, and inhibits its activity. Inhibition of calcineurin activity prevents the activation of transcription factors such as nuclear factor for activated T cells, which are essential for the production of interleukin 2 and probably other T cell responses to antigen. CsA produces incomplete calcineurin phosphatase inhibition in lymphocytes of CsA-treated patients. Peak CsA levels produce 70–90% calcineurin inhibition, which closely correlates with the rise and fall of CsA levels with no lag time. Additional studies have shown that in renal transplant patients receiving CsA, there is a strong relationship between renal function and the rise and fall of CsA levels. The nadir of glomerular filtration rate occurs 2–4 hours after the maximal CsA levels and returns to baseline by the end of the 12-hour dosing interval.11 Accordingly, both calcineurin phosphatase inhibition and nephrotoxicity seem to be closely correlated to Cmax. The introduction of Neoral, with its superior absorption characteristics and greater exposure often not reflected in trough level measurements, has led to an intense evaluation of the traditional approach to TDM of CsA, based on measurements of C0. Kahan et al. have demonstrated that full AUC monitoring is the most sensitive and precise indicator of drug exposure.12 They showed that AUC values less than 25% of the cohort and clearance values greater than 1500 mL/min were associated with high rates of renal transplant rejection and worse graft survival. They further showed that intrapatient variability greater than 20% over time was a significant risk factor for the development of chronic rejection. In patients with low variability, 10-year graft and patient survival exceeded 90%, whereas when the variability was high, graft and patient survival was only 57%. Although these results supported a role for full AUC monitoring, both the practical difficulties and expense associated with that approach have led to a search for alternative methods, including the use of sparse sampling algorithms. Prospective studies in liver transplant recipients have demonstrated that absorption of Neoral is relatively independent of bile flow and food intake and provides increased AUC with Cmax and no increase in toxicity.13 A pivotal study in liver patients (NOF 8) showed that in Neoral-treated patients who achieved Cmax levels greater than 800 ng/mL or AUC0–6 greater than 3300 ug.h/L, the rate of rejection was approximately 25%. C2 proved to be an excellent surrogate marker for both AUC0–6 and Cmax (r2 = 0.93). The correlation of C0 with both AUC0–6 and Cmax was poor, and no relationship could be found between C0 and freedom from rejection even when C0 levels approached or exceeded 450 ng/mL.14 This study set the stage for an international multicenter study that was conducted in de novo liver transplant recipients to compare the benefits of C2 and C0 monitoring.15 At three months posttransplantation, the C2 group had a 25% reduction in the incidence of acute rejection, compared with the C0 group (24% vs. 31%, P = .06), and the incidence of moderate to severe acute rejection was significantly lower in the C2-monitored group compared with the C0 group (P = .01). Interestingly, tolerability profiles were similar between the two groups up to one year posttransplant, despite the high levels in the C2 group, with no difference in renal function and a trend to reduced steroids among C2 monitored patients. The studies conducted in liver transplant patients led to pivotal studies' being conducted, particularly in renal transplant recipients, but also in heart and lung transplant recipients, providing strong evidence that C2 was the single point correlating best with AUC0–4 and with clinical events.16 Recent international studies have shown that the use of C2 monitoring results in rejection rates of approximately 10% in de novo renal transplant recipients.17, 18 Limited studies have now been conducted in lung, heart, and pediatric patients, demonstrating the utility of C2 monitoring as a predictor of AUC and freedom from rejection. The improved correlation between C2 and clinical events may relate both to its improved correlation with overall exposure and also to the fact that it is the single value that correlates best with Cmax. The question of whether similar benefits may be achieved through the adoption of Neoral C2 monitoring in maintenance transplant patients is an important issue, since the major challenge relating to long-term management of liver transplant patients is chronic toxicity including unacceptably high rates of renal dysfunction, which contributes to patient mortality. Chronic rejection is much less important as a cause of both morbidity and mortality. In this issue of Liver Transplantation, Langers et al. have examined the influence of switching CsA monitoring from C0 to C2 in stable liver transplant patients on CsA dose, renal function, blood pressure, rejection, and relation to AUC0–12.19 Patients who were monitored by C0 were converted to C2 monitoring, and the dose of CsA was adjusted to bring C2 target levels to 600 ±15% ug/mL. To achieve this, CsA levels were reduced in 21 patients and remained unchanged in 10, resulting in a mean daily dose lowering of 69 mg. This resulted in an increase in creatinine clearance of 7.93 mL/min and an improvement in morning systolic blood pressure. C2 was found to correlate better with AUC0–12 than C0. Following conversion, 13 out of 21 patients were found to have a second AUC below target, and 2 of these patients developed acute cellular rejection. The data presented by these authors is consistent with studies showning that greater than 40% of long-term renal and liver patients are overexposed with AUC and C2 levels in excess of recommended levels, despite C0 levels' being within target range.20, 21 In those studies, there was a weak relationship between C0 and C2 shown by linear-regression studies, suggesting that C0 could not be used to predict overexposure. When C2 levels were reduced to proposed targets in both renal and liver patients, there was a reduction in hypertension, cholesterol and triglyceride levels, tremor, nephrotoxicity, gum hyperplasia, and hirsutism. Furthermore, when levels were adjusted to recommended targets, patients commented that they felt better. No acute rejection occurred with a mean follow-up time of 15 months in the renal series and 12 months in liver transplant recipients. While the results of those open studies showed that C2 monitoring and adjustment to these predetermined targets improved clinical parameters in many individuals, no data is yet available describing what the optimal CsA exposure and C2 levels are over the long-term in liver or other organ transplant recipients. Studies by Citterio et al., however, in patients on CsA and prednisone alone have suggested that low C2 levels may be associated with chronic allograft rejection, whereas higher exposure was protective.22 The finding in the Langers article, that 2 patients developed acute rejection, and that these 2 patients had an AUC0–12 below the range defined as being optimal is of some concern, although the number of patients studied was small. It is also difficult to interpret the significance of these rejection episodes without knowing whether the patients were at higher than normal risk (e.g., autoimmune liver disease or previous transplant rejection). Other data has suggested that up to 10% of liver patients may experience acute rejection between 6 and 12 months posttransplant when monitored by C0.23 The authors infer in the present study that these patients were underexposed to CsA because the AUC0–12 was below target. However, the target AUC was derived from C0 data, which are known to not accurately reflect AUC.24 As C2 has been shown to correlate better with AUC, it would be of interest to know the C2 values in these patients to compare their AUC with a C2-derived range for this parameter. Furthermore, as most postdose variability occurs in the first 4 hours, we believe that the AUC0–4, as suggested by Pollard et al., is preferable to AUC0–12 in reflecting clinical events and would have been interesting to use in these studies.24 While we do not agree that this study proves that C2 monitoring is associated with increased rejection, even if it were, the long-term benefits of reduced toxicity might well outweigh the development of mild, easily treated rejection in a small number of patients. The authors conclude that C2 monitoring is more likely to be associated with underdosing than is C0. This should not be true unless C2 values are more variable than C0 or unless C2 is a less accurate measure of exposure, neither of which has be shown to be true. Having said that, it is clear to us that additional studies are needed to determine the optimal C2 targets at different time points posttransplant to be certain that exposure is maintained above these levels. Such targets may also need to be individualized to time posttransplant and immunologic risk of the recipient. Other issues that will need to be explored include the choice of the measuring assay and the source of the samples to be assayed. Today there are a number of assays available for measurement of CsA. When compared with high-pressure liquid chromatography, it is apparent that many of these assays do not give an accurate measure of parent drug, although this may be less relevant at the 2-hour postdose time point, since there are only low levels of CsA metabolites that could cross-react in the assay. For over two decades, we have empirically used C0 to monitor CsA levels, in an attempt to maximize efficacy and minimize toxicity. It is now clear from pharmacokinetic and clinical studies that the use of this monitoring strategy is not sufficient as a predictor of either of these clinical outcomes. C2 monitoring appears to be a highly sensitive and more accurate predictor of clinical outcomes having a close correlation with important pharmacokinetic parameters including AUC and Cmax. We believe that this study does not negate the utility of C2 but rather emphasizes the point that more data are required to optimize its use in clinical transplantation. TDM, therapeutic drug monitoring; CsA, cyclosporine; AUC, time concentration curve; Cmax, maximum concentration of CsA post-dose.

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