Clinical validation studies of neoral C2 monitoring: a review

Although cyclosporine A (CsA) has been the mainstay of immunosuppressive therapy and the subject of intense investigation for more than 20 years, it is only recently that the full potential of the drug has come to be understood. This is primarily owing to two advances: first, the development of an improved microemulsified formulation, Neoral, to improve drug delivery; and second, substantial improvements in the monitoring of CsA, which is the focus of this article. It has been clear for many years that CsA, as a drug with a low therapeutic index, requires individualized monitoring of blood concentration. In the past, standard trough-level (C0) monitoring has been used. Although this method is currently the routine strategy, it became evident after the development of Neoral that the improved bioavailability of the new formulation was not reflected by a change in the trough concentration (1,2). Subsequent work also showed convincingly that whereas CsA exposure determines the extent of immunosuppression and toxicity, drug exposure did not correlate closely with C0 (3,4). Interpatient variability in CsA exposure is greatest during the absorption phase (up to 4 hours after a dose of Neoral), and adequate exposure during this absorption phase is critical for CsA efficacy. Neoral C2 monitoring, whereby absorption of CsA is measured by a single sample taken 2 hours postdose, is the result of an extensive program of research into the optimal use of Neoral (5–8). This research has focused on delivery of individualized dosing to achieve minimal rejection with minimal toxicity. The well-documented pharmacokinetic rationale for using C2 to monitor patients receiving Neoral (3,4,10–13) has now been borne out by clinical trials that demonstrate a reduced incidence and severity of rejection in de novo patients (14–17) and improvements in safety profile, particularly renal function, in both renal and hepatic maintenance patients (18,19). This article is a critical review of the most recent clinical evidence for the use of Neoral C2 monitoring as a management tool in different transplant populations. THE RATIONALE FOR NEORAL C2 MONITORING Pharmacokinetic Rationale CsA is a highly lipophilic molecule with wide interpatient and intrapatient variation in absorption (5). Low oral bioavailability of CsA is recognized as a significant risk factor for acute rejection, (6) and high variability in systemic exposure to CsA is associated with an increased risk of chronic rejection in renal transplant patients (7). These pharmacokinetic challenges have been improved with the Neoral formulation of CsA. Neoral provides increased and more consistent systemic exposure compared with the original cyclosporine formulation (Sandimmune; Novartis Pharmaceutical Corp., East Hanover, NJ) (8), with reduced variability in the shape of the area under the concentration-time curve (AUC) and time to peak concentration (tmax)(1,8). Pharmacokinetic analysis (20) of patients receiving Neoral has shown that the greatest interpatient and intrapatient variability in CsA absorption occurs during the first 4 hours after dosing. This absorption phase is crucial because it represents the ability of an individual to absorb adequate CsA to ensure effective immunosuppression. Thus, a monitoring strategy that aims to reflect differences in exposure between individuals should focus on this early absorption phase after Neoral dosing. Pharmacodynamic Effect of CsA The potential value of CsA blood concentration monitoring during the first few hours after administration of Neoral has been endorsed by pharmacodynamic evidence showing that the immunosuppressive effect of CsA is maximal and most consistent around the peak absorption time, that is, within the first 1.5 to 2.5 hours postdose (21–23). Halloran et al. (21) have shown that the immunosuppressive action of CsA (the inhibition of calcineurin in lymphocytes) is correlated with blood concentration and peaks at approximately 2 hours after Neoral administration. Furthermore, in a recent study (22) of renal transplant recipients receiving Neoral-based immunosuppression, there was a significant decrease in the proportion of lymphocytes expressing interleukin (IL)-2 at 2 hours postdose (C2 time point), compared with the C0 time point (3% at C2 versus 15% at C0,P <0.05). Clinical Significance of Neoral Absorption Profile Pharmacokinetic studies from the Halifax group (3,9) have confirmed the predictive value of CsA absorption profiling in clinical practice. In a retrospective study (3) of 156 renal transplant patients treated with Neoral, drug dosage was modified according to C0 level, but area under the concentration-time curve in the first 4 hours after administration (AUC0–4) values were also collected on days 3 to 5 posttransplant. The AUC0–4 value during the first week posttransplant was predictive of acute rejection (P =0.006), whereas C0 showed no significant correlation with rejection. Patients with low exposure (AUC0–4 <4400 μg.h/L) had a high incidence of rejection, whereas those with high exposure (AUC0–4>5500 μg.h/L) had a higher incidence of nephrotoxicity. Accordingly, an optimal range of exposure (AUC0–4 4400–5500 μg.h/L) was proposed to minimize both rejection and nephrotoxicity. A subsequent prospective study (9) of 55 de novo renal transplant patients, in which Neoral exposure was targeted to this AUC0–4 range, found that only 3% of patients who achieved target AUC0–4 by day 3 experienced acute rejection by 3 months, compared with 45% of those who did not reach target AUC0–4(P =0.0002) (Figure 1). As in their retrospective analysis (3), these researchers found no correlation between C0 and the incidence of acute rejection. Furthermore, there was no negative effect of reaching AUC0–4 target on renal function: indeed, mean serum creatinine at 3 months was lower in patients who achieved target AUC0–4 early, compared with those who did not (P =0.001).Figure 1: Incidence of acute rejection at 3 months posttransplant in 55 de novo renal patients in whom Neoral dose was adjusted on the basis of AUC0–4 (area under the concentration-time curve in the first 4 hours after administration). Patients achieving AUC0–4 target (4400–5500 μg.h/L) by day 3 experienced a very low risk of acute rejection (3%).(9)C2 as an Accurate Single-Sample Marker for AUC0–4 in Patients Receiving Neoral Although AUC0–4 is a sensitive marker for CsA absorption, it requires multiple, timed blood samples, making it impractical to use for routine patient management. Numerous analyses (4,10–13) have evaluated CsA concentration at various time points to identify the single sample that provides the most accurate surrogate marker for AUC0–4. These analyses have consistently shown that the 2-hour postdose sampling point (C2) correlates most closely with AUC0–4 in both the early (4,10,13) and later posttransplant periods (10–13). Results from adult renal (3), liver (1), and cardiac (11) patients, as well as pediatric renal (12) and liver (13) transplant recipients, have demonstrated a correlation coefficient (r2) of >0.80 for C2 and AUC0–4. As in the Halifax studies (3,9), each of these studies found a relatively poor correlation between C0 and AUC0–4 (r2<0.50). For example, in an international 3-month prospective study (10) conducted in 204 de novo renal transplant recipients from 20 transplant centers, the most sensitive surrogate marker for AUC0–4 was the C2 sampling point (r2=0.67–0.85), and the least sensitive was C0 (r2=0.04–0.25) throughout the first 3 months posttransplant (Figure 2). Moreover, C2 was consistently the best surrogate marker for Cmax (the peak concentration of CsA) at all time points measured during the study (days 3, 7, 14, and 84). As stated earlier, Cmax is known to coincide with the peak pharmacodynamic effect of Neoral (21–23), such that C2 is not only a sensitive measure of Neoral absorption but may also be an accurate index of immunosuppression.Figure 2: Correlation between AUC0–4 (area under the concentration-time curve in the first 4 hours after administration) and single time-point samples of CsA concentration (C0, C1, C2, C3, and C4) in 204 de novo renal transplant recipients receiving Neoral, by time of posttransplant (10). The C2 time-point consistently showed the closest correlation with AUC0–4 out of all single time-points evaluated.Summary In summary, data from several studies using Neoral in de novo renal and liver transplant recipients have identified the following: Adequate and consistent absorption of CsA is critical for optimal outcome. The greatest variability in CsA absorption occurs in the first 4 hours after administration of Neoral (AUC0–4). The maximal immunosuppressive effect of Neoral also occurs during this period. AUC0–4 is a highly sensitive predictor of acute rejection but is impractical to use as a routine monitoring tool in the clinic. C0 (trough CsA concentration) correlates only poorly with AUC0–4 (r2<0.50). C2 (CsA concentration at 2 hours after administration of Neoral) is the most accurate single-sample marker for AUC0–4, with a correlation coefficient of r2>0.80 across all tested transplant patient populations. NEORAL C2 AS A PREDICTOR OF ACUTE REJECTION RISK Multicenter Trial Results The Canadian Neoral Renal Transplantation Study Group has reported an evaluation of the relationship between CsA C2 levels using Neoral and risk of acute rejection in 38 renal transplant recipients (4). Pharmacokinetic data were recorded on days 3, 7, and 14 posttransplant. Mean C2 at day 7 was significantly higher among patients who remained rejection-free by day 14 compared with those who experienced rejection (1.9±0.5 μg/mL vs 1.1±0.2 μg/mL;P <0.0001). It is striking to note that patients who achieved C2 >1.5 μg/mL by day 7 posttransplant experienced no rejection, whereas 58% of those with C2 <1.5 μg/mL experienced at least one rejection episode by day 14 (P <0.001) (Figure 3).Figure 3: Incidence of acute rejection at day 14 posttransplant among 38 de novo renal transplant recipients according to Neoral C2 value at day 7 (4). No acute rejection episodes occurred by day 14 among patients with C2>1.5 μg/mL at day 7.In liver transplantation, the Canadian Liver Transplant Study Group (1) has explored the relationship between CsA pharmacokinetics and acute rejection. Patients receiving Neoral (n=95) were divided into quartiles based on Cmax at day 15 posttransplant. The quartile group with the highest Cmax (>1.2 μg/mL) exhibited the lowest incidence of acute rejection at 6 months posttransplant, while the quartile with the lowest Cmax (<0.6 μg/mL) had the highest rate of rejection (31% versus 71%, P =0.019). In a prospective international study of Neoral C2 monitoring in liver transplant patients (INT-06) (17), Cox regression analysis of data from 307 transplant patients at 3 months posttransplant showed that Neoral dose and C0 were not significantly predictive (P >0.15 and P =0.17) of acute rejection risk, but C2 was significant (P =0.04). Single-Center Trial Results The predictive value of C2 has recently been examined by the Halifax group (24) using receiver operating characteristic curve (ROC) analysis of data from 98 de novo renal transplant patients. The analysis included an assessment of the predictive value of C0 and C2 at day 3 posttransplant for acute rejection occurrence within 6 months. The ROC analysis validated C2 as a significant predictor for acute rejection (P =0.004), whereas C0 demonstrated no predictive value (P =0.64). The ROC analysis also identified that a C2 value of 1.7 μg/mL was a critical cutoff point on the ROC curve. Patients who reached 1.7 μg/mL by day 3 had a 92% chance of remaining rejection-free. The predictive value of Neoral C2 has been corroborated in another retrospective study (25) that analyzed the relationship between Neoral pharmacokinetic parameters and the incidence of acute rejection. Among 122 de novo renal transplant recipients, the mean C2 level achieved at days 3 to 5 was significantly lower in patients who had an acute rejection episode (38% of the population) than in those who remained rejection-free (0.86 μg/mL vs 1.06 μg/mL, P of Neoral C2 in Patients Receiving The predictive of Neoral C2 for risk of acute rejection has been evaluated within a of de novo renal transplant patients receiving months episodes of rejection had analysis showed that C2 was a predictor of rejection (P <0.0001). No pharmacokinetic C0 (P rejection. Patients with mean C2 μg/mL had a risk of acute those with a mean C2 >1.5 μg/mL had only a 15% risk of rejection. A study has corroborated the predictive value of C2 for acute rejection in patients receiving an (10). The analyzed from 204 de novo renal transplant recipients receiving Neoral, and the first 3 months posttransplant. patients were into high of Neoral based on C2 poor with C2 values μg/mL at day 3 had approximately of remaining rejection-free at 3 months, compared with only of those with C2 μg/mL (Figure of from acute rejection among poor of cyclosporine (CsA) by CsA C2 level using Neoral at day 3 posttransplant. C2 levels were associated with a higher of from rejection studies that the of an to a Neoral-based not have an on the of Neoral C2 monitoring as a predictor for acute rejection in the de novo renal transplant Neoral C2 is highly predictive of acute risk of rejection in renal and liver adult transplant patients during the early posttransplant period. Multicenter and studies have consistently shown that C2 levels significantly and correlated with of from rejection 1: of trials Neoral C2 as a predictor of acute rejection predictive value of C2 for acute rejection is not by with an OF NEORAL C2 MONITORING Results from Multicenter and Single-Center The of 2-hour Absorption in Renal Transplantation study is the first study to the and safety of Neoral C2 monitoring in de novo renal transplant patients. The of the is to the optimal target C2 levels during months 3 to posttransplant, in patients receiving Neoral, and Neoral C2 to μg/mL during to μg/mL during and to μg/mL during 3, and Neoral dose is individualized in each patient to for these 3, patients to one of two C2 target Group to μg/mL for months 4 to to μg/mL for months 7 to Group to μg/mL for months 4 to to μg/mL for months 7 to In patients with C2 be reduced and an used. from of the patients, with a of days The incidence of acute rejection at 3 months among this group of patients was (Figure Among the patients with achieved target C2 levels by day and the incidence of acute rejection at 3 months was only in the In the patients who experienced the incidence of acute rejection at 3 months was Incidence of acute rejection at 3 posttransplant among de novo renal transplant recipients by Neoral C2 monitoring data from of 2 Absorption in Renal Transplantation Neoral C2 were to μg/mL during to μg/mL during and to μg/mL during In patients with C2 be was of prospective trials of Neoral C2 monitoring in de novo renal out at single to the of the 2). In a study of Neoral C2 monitoring in renal transplant patients only of the patients who achieved C2 μg/mL in the first posttransplant experienced an acute rejection episode compared with of patients with In another study de novo patients by C2 monitoring using an C2 target of 1.7 μg/mL in with to a target of μg/mL from had only a incidence of acute rejection 6 2: of prospective trials of Neoral C2 monitoring in de novo transplant of Neoral C2 data from the study have shown that among de novo renal patients the mean serum creatinine levels achieved at months and 3 were were only of and no patient Neoral therapy creatinine levels to 6 months posttransplant from a analysis of de novo renal transplant patients by Neoral C2 monitoring and a group of by C0 monitoring Neoral patients were to achieve C2 levels of 1.7 μg/mL by day 5 posttransplant with a in C2 target to μg/mL from 6 months. was no in mean serum creatinine between the C2 and C0 at time point during the study reported and were between the two of was more in the C2 3: Mean serum creatinine in de novo renal transplant patients by Neoral C2 C0 monitoring another study of renal transplant patients by Neoral C2 monitoring only one patient in the group who achieved μg/mL nephrotoxicity. area of associated with monitoring of Neoral has been the use of a higher dose of Neoral may renal and in patients who This has been in a of C0 monitoring and Neoral absorption monitoring by AUC0–4 in de novo renal transplant recipients with The time to from was 3 days in the group compared with days in the group a significantly higher dose vs P in the AUC0–4 group at week 4 the mean serum creatinine was significantly lower in the AUC0–4 group versus P and this was at 3 months posttransplant versus These that the for higher Neoral in in to adequate absorption during the early posttransplant not renal in patients C2 levels 1.5 μg/mL during the early posttransplant is associated with a low incidence of acute rejection episodes in de novo renal transplant Renal is not by Neoral C2 monitoring compared with C0 monitoring in patients with in those with OF NEORAL C2 MONITORING Results from Multicenter and Single-Center The international was the first prospective study to individualized Neoral dosing based on C2 versus C0 monitoring in liver transplant This was a study 307 de novo liver transplant recipients from Neoral C2 target range was to C0 target range was to included incidence and severity of acute rejection at 3 and months. The incidence of acute rejection at months was lower in the C2 compared with the group versus this was not was a significant in the proportion of rejection episodes as and in the C2 group compared with the C0 group compared with P This is of because there is evidence that only and rejection episodes associated with poor and liver It is also significant that the 3-month rejection rate was only among patients who achieved target C2 levels by day 3 posttransplant whereas patients reaching target by day 7 (n=95) had a rejection rate of (P (17), the to achieve target C2 in the first days posttransplant. Mean dose was lower in the C2 group compared with in the C0 and at months only of patients to compared with of patients by C0 monitoring (P Clinical of de novo liver transplant recipients by Neoral C2 C0 monitoring compared with Neoral C2 is a monitoring strategy, to a lower incidence of acute rejection and rejection, which be to improve A prospective has evaluated the clinical of Neoral C2 monitoring in de novo liver Neoral administration was at 15 and the dose was adjusted to target a C2 level of to μg/mL within 3 to 5 days of day 3, of patients achieved target and all patients had achieved target values by day 5 posttransplant. incidence of rejection of was and the rejection episodes were 3 and by This study the clinical achieved using Neoral C2 monitoring in the de novo liver transplant of Neoral C2 In the study which compared Neoral C2 versus C0 monitoring, serum creatinine levels were in the C2 and C0 at months (C2 C0 group and there were no differences in serum creatinine levels between the at point during the only of patients in group had a serum creatinine value were there differences in the incidence of between the two The of de novo liver transplant recipients conducted in found no renal a high dosing creatinine levels remained within the range at day posttransplant of Neoral C2 with A prospective study has been out in liver transplant patients, Neoral C2 monitoring with therapy using C0 monitoring Patients Neoral to achieve C2 target μg/mL) to achieve in with The incidence of rejection at 6 months was reduced in patients receiving Neoral versus those receiving compared with P patients in the group to rejection, whereas rejection episodes in patients receiving Neoral were with patients receiving renal and patients The incidence of posttransplant was in the group and in the Neoral group (P <0.05). was no significant in the incidence of Neoral C2 monitoring in de novo liver the incidence and severity of acute rejection compared with C0 is no in renal between Neoral C2 monitoring and C0 evidence that patients by Neoral C2 monitoring may a significantly lower incidence of acute rejection and a reduced incidence of compared with patients treated with NEORAL C2 MONITORING Clinical and Neoral C2 The of Neoral C2 with clinical to be evidence has that Neoral C2 is an effective marker for risk of chronic A retrospective study has the relationship between C2 levels and incidence of in maintenance renal transplant recipients receiving Neoral and time posttransplant 55 Neoral dose was adjusted based on with a target of and full CsA pharmacokinetic were collected from each patient a and C2 the time of 20 patients (the had as serum creatinine confirmed the of chronic rejection in 14 of these patients. In the remaining patients (the there was no evidence of The group had experienced acute rejection episodes compared with 45% in the but there were no differences between the two in of time the time of mean C0 level was and mean C2 level was μg/mL across the patient The mean C2 level in the group was significantly higher than in the group μg/mL versus μg/mL, P that there is a relationship between C2 levels and mean C0 level did not correlate with the of in the group versus in the of Neoral C2 in Renal Transplant Patients The effect of Neoral C2 monitoring in maintenance renal patients by C0 monitoring has been in a group of patients, all of whom were more than 3 months posttransplant Neoral dose was reduced in patients C2 target level months, months, months, μg/mL) by more than patients had C2 levels target at the time C2 monitoring was and Neoral dose was reduced in these patients, from a mean of to with a mean of months. No episodes of acute rejection occurred in of the patients in whom Neoral dose was Among the patients in whom Neoral dose was mean serum creatinine from at the time of to at (P (Figure Mean blood among patients also improved from at the time C2 monitoring was to (P for blood of patients who a dose reported an in of Mean serum creatinine among maintenance renal transplant patients in whom Neoral dose was reduced because C2 levels target by shown of Neoral C2 monitoring and at time of patients were months posttransplant and had been by Neoral C0 Neoral C2 were 3 to 6 months, 6 to months, months C2 levels using Neoral lower in patients with than in patients with CsA is a occurrence in maintenance renal patients by C0 of Neoral C2 monitoring in maintenance renal transplant patients improve renal and blood in patients in whom to CsA has remained by C0 monitoring, and in whom Neoral dose is NEORAL C2 MONITORING of Neoral C2 in Liver Transplant Patients The clinical of Neoral dose using C2 monitoring in maintenance liver transplant patients has been in a study of recipients who had been by C0 monitoring months The for of C2 monitoring was CsA The for C2 monitoring that Neoral dose should be adjusted to achieve C2 months, months months, the point at which C2 monitoring was mean C0 was and mean C2 was In of patients were found to have C2 levels and the Neoral dose was adjusted to these patients within target using the No patients experienced rejection as a result of dose 3 months of C2 monitoring, there was a mean decrease in serum creatinine of (P <0.001) from to among patients receiving a dose in serum creatinine were in patients to years posttransplant. there was a mean decrease in blood of 14 (P C2 to of Neoral C2 monitoring in maintenance liver transplant recipients for Neoral dose in patients to CsA, with improvements in renal and blood OF NEORAL C2 MONITORING A study of and the of 5 years has shown that individuals with absorption of CsA lower The improved of CsA absorption using Neoral C2 monitoring be to a in posttransplant management compared with C0 This was by a analysis based on for clinical from two prospective studies de novo renal transplant recipients by Neoral C2 C0 The incidence of acute rejection at was in the C2 group and in the C0 were using a Canadian The patient for the first posttransplant was to be for Neoral C2 monitoring and for C0 monitoring, a of with Neoral C2 monitoring during analysis that a in of and and the reduced risk of acute rejection, were most in to the associated with Neoral C2 Neoral C2 monitoring is to as early as the first posttransplant. in with Neoral C2 monitoring to be associated with reduced for and lower incidence of acute rejection. A range of clinical trials have now confirmed that Neoral C2 monitoring is a strategy compared with C0 monitoring in the of acute rejection in de novo renal and liver transplant Neoral C2 monitoring is well in de novo patients and to have no effect on renal studies have demonstrated the clinical of Neoral C2 monitoring in the maintenance renal and liver of Neoral C2 monitoring to CsA, to dose with improvements in renal and blood evidence from retrospective studies that Neoral C2 monitoring may the risk of prospective studies to analysis has that Neoral C2 monitoring is to be compared with C0 studies to the of Neoral C2 monitoring in hepatic and renal transplant patients. In the potential in and transplantation, and in pediatric transplant recipients, to be in prospective clinical evidence that Neoral C2 monitoring represents a of immunosuppression.

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