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NDT Advance Access originally published online on October 4, 2005
Nephrology Dialysis Transplantation 2006 21(1):197-202; doi:10.1093/ndt/gfi113
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Evolution of the absorption profile of cyclosporine A in renal transplant recipients: a longitudinal study of the de novo and maintenance phases

Matthias Büchler1, Steve Chadban2, Edward Cole3, Karsten Midtvedt4, Eric Thervet5, Hans Prestele6 and Paul Keown7

1 Department of Nephrology and Clinical Immunology, C.H.U. Tours, Tours, France, 2 Royal Prince Alfred Hospital, Sydney, Australia, 3 Renal Transplant Program, Toronto General Hospital, Toronto, Canada, 4 Medical Department of Nephrology, Rikshospitalet, Oslo, Norway, 5 Department of Renal Transplantation and Intensive Care, Hôpital Necker, Paris, France, 6 Novartis Pharma AG, Basel, Switzerland and 7 Department of Medicine, University of British Columbia, Vancouver, Canada

Correspondence and offprint requests to: Dr Matthias Büchler, Department of Nephrology and Clinical Immunology, C.H.U. Tours, 2 Boulevard Tonnellé 37044 Tours, France. Email: buchler{at}med.univ-tours.fr



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Therapeutic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using either trough levels (C0) or levels at 2 h post-dose (C2). This analysis assessed changes in C0 and C2 and their relationship to CsA-ME dose over time post-transplant in renal transplant patients.

Methods. Data were obtained from MO2ART, a prospective multicentre trial in which CsA-ME dose was adjusted based on C2 level. All 98 patients in whom C0 and C2 were available at day 5, month 3 and month 12 were included, out of 234 who completed the 12 month study. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was calculated, together with C0/ND, C2/ND and C2/C0.

Results. C0/ND and C2/ND both increased between day 5 and month 3: C0/ND from 33±15 to 53±24 (ng/ml)/(mg/kg) and C2/ND from 161±64 to 248±80 (ng/ml)/(mg/kg). Between month 3 and month 12, C2/ND remained stable but C0/ND decreased to 42±20 (ng/ml)/(mg/kg) while the C2/C0 ratio increased from 5.2±1.9 to 6.5±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (45 vs 32%, P<0.05) and at 12 months (48 vs 31%, P<0.01).

Conclusions. CsA clearance accelerates between months 3 and 12 post-transplant, resulting in lower C0 levels for a given exposure (as measured by C2). As a consequence, C0 monitoring may progressively underestimate CsA exposure during the first year post-transplant. C2 monitoring contributes to improved individualized CsA-ME treatment in both the de novo phase and beyond month 3.

Keywords: absorption; C2 monitoring; cyclosporine microemulsion; renal transplantation



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Recent years have seen an intensive research effort directed towards improving the therapeutic drug monitoring of immunosuppressive agents [1]. In particular, attention has focused on cyclosporine (CsA) [2–4], with the goal of ensuring appropriate CsA exposure in individual recipients of solid organ transplants.

Inter-patient variability in CsA blood levels is highest within the first 4 h post-dose, when CsA absorption predominates. CsA exposure within the first 4 h (AUC0–4) after administration of cyclosporine microemulsion (CsA-ME) is predictive of acute cellular rejection within the first 3 months post-transplantation [5]. CsA blood concentration 2 h after dosing (C2) is the single time-point that correlates most closely with AUC0–4, and C2 values have been shown to correlate with inhibition of calcineurin [6] and risk of acute rejection [7]. In contrast, conventional trough (C0) measurements of CsA blood concentration correlate only poorly with AUC0–4 [7,8] and C0 is not a sensitive marker for risk of rejection [5]. Nevertheless, C0 monitoring is still used in many transplant centres because adoption of C2 monitoring requires logistical changes within transplant units, and because blood samples for C2 monitoring must be collected within a 30 min window (i.e. 2 h±15 min post-dose).

More recently, some authors have argued that a combination of C2 and C0 monitoring could be a useful technique for evaluating the absorption profile of cyclosporine more precisely, since it takes into account both the absorption phase (C2) and the elimination phase, including metabolism (C0). The C2/C0 ratio has also been used to identify high or low absorbers of CsA [10].

Finally, several studies have evaluated the influence of the intra-individual coefficient of variation of either the C0 or C2 on clinical events [11–13]. However, most of these trials had important limitations, notably use of the oil-based formulation of CsA and recording pharmacokinetic parameters at variable time-points.

The aim of our study was to analyse changes in pharmacokinetic parameters for CsA-ME over the first year post-transplant in renal transplant patients. We analysed C2 and C0 together with their relationship to the weight-adjusted dose of CsA-ME and to each other. Additionally, we studied the intra-individual stability of these parameters and the inter-individual coefficient of variation up to 1 year post-transplant.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
The analysis was based on data collected in the MO2ART study (Monitoring Of 2 hours Absorption in Renal Transplantation), a prospective, randomized, multicentre study in which de novo renal transplant patients were managed by C2 monitoring of CsA-ME. Details of the study design and findings have been published previously [4,14]. All patients received CsA-ME b.i.d., starting within 24 h post-transplantation at a dose of 10 mg/kg, in conjunction with steroids and mycophenolate mofetil or azathioprine. The C2 target was 1600–2000 ng/ml during month 1 and 1200–1400 ng/ml for months 2 and 3. At the end of month 3, patients entered randomized groups in which C2 targets were lower (800–1000 ng/ml during months 4–6; 600–800 ng/ml during months 7–12) or higher (1000–1200 ng/ml during months 4–6; 800–1000 ng/ml during months 7–12). Blood samples for the central laboratory were collected before dosing (C0) and 2 h post-dose (C2) on day 5 and at months 3 and 12. CsA concentrations were determined using the specific reagents of the INCSTAR Cyclo-Trac® SP-Whole Blood radioimmunoassay kit, based on whole-blood samples. CsA-ME dose, body weight and other parameters including locally determined laboratory values were obtained from the MO2ART database for each of the three time-points.

The analysis included all 98 patients for whom centrally determined values for C0 and C2 were available at day 5, month 3 and month 12. At each time-point we calculated the CsA-ME dose per kilogram body weight (normalized dose, ND), and the ratios C0/ND, C2/ND and C2/C0. The interpatient coefficient of variance (CV) for C0/ND and C2/ND was calculated across all patients at each of the three time-points. Intra-individual CVs were not calculated because only two samples per patient were available for the maintenance period (months 3 and 12). Instead, intra-individual stability was assessed by calculating individual ratios between the month 3 and month 12 values for C0/ND, C2/ND and C2/C0.

Fisher's exact test, t-test and Wilcoxon rank sum test were used for between group comparisons. The paired t-test was used to compare intra-individual changes over time. To account for the different individual levels, relative changes from month 3 to month 12, in percentage of the month 3 values, were also determined. Confidence intervals were used for the assessment of the inter-patient CV.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Two hundred and ninety-six patients were recruited to MO2ART. Of the 234 patients who completed the 12 month trial, 98 provided C0 and C2 blood samples on day 5, month 3 and month 12 to the central laboratory and were included in this analysis. No reason could be found why incomplete or no samples were provided for the remaining patients, other than centre non-compliance, and there were no significant differences in demographics or baseline characteristics between patients who completed the study and did or did not provide a full set of blood samples (Table 1). Of the included patients, 91 started on mycophenolate mofetil and 7 on azathioprine as an adjunctive agent. Patients with delayed graft function (DGF) were less likely to continue the study until month 12 than those with immediate function (67 vs 86%), such that the proportion of patients with DGF was lower in our cohort than the overall MO2ART study population.


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  		Table 1. Patient demographics and baseline characteristics of patients completing the 12-month MO2ART study, according to inclusion or exclusion from current analysis

 
The dose of CsA-ME and CsA concentrations were greatest early post-transplant, declining thereafter in line with decreasing C2 target ranges (Figure 1 and Table 2). When the same analysis was undertaken separately for patients entering the higher-C2 target group (59/98) or the lower-C2 target group (39/98) after month 3, there were no differences compared with the overall analysis (Table 3). The relationship between C0 and C2 levels and weight-normalized dose, expressed by C0/ND and C2/ND, increased significantly between day 5 and month 3 (Table 2 and Figure 2). This was expected and confirms the well-known increase in drug absorption early after renal transplantation. Between month 3 and 12, CsA-ME dose as well as absolute C0 and C2 levels decreased further. While the relationship between C2 and CsA-ME dose (C2/ND) remained stable (median –3%), the decrease of C0 levels was more marked, resulting in a net decrease of C0/ND and an increase in the ratio of C2/C0 (Figure 2 and Table 2). This effect appeared not to be linked to the CsA-ME dose: when patients were stratified into tertiles according to weight-adjusted CsA-ME dose at month 12, the C2/C0 ratio was 6.6±2.9, 6.2±1.9 and 6.8±2.2 for patients receiving <2.7, 2.7–3.5 or ≥3.5 mg/kg CsA-ME, respectively (n.s.).



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  		Fig. 1. Mean CsA-ME dose, mean C2 and mean C0 levels at day 5, month 3 and month 12 post-transplant (n = 98).

 

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  		Table 2. Pharmacokinetic parameters at day 5, month 3 and month 12

 

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  		Table 3. Pharmacokinetic parameters at month 3 and month 12 for patients in higher-C2 cohort (n = 59) or lower-C2 cohort (n = 39) after month 3

 


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  		Fig. 2. Distribution of pharmacokinetic parameters at day 5, month 3 and month 12 post-transplant (n = 98).

 
There was no significant difference in pharmacokinetic parameters when patients were stratified by gender, age, presence or absence of DGF, or pre-existing diabetes.

Patients who discontinued steroids between month 3 and month 12 (n = 19) showed a significant increase in C2/ND ratio, while this relationship remained unchanged in those who continued to receive steroids. The significant increase in C2/C0 between month 3 and month 12 was present in all patients regardless of whether steroids were continued or discontinued (Table 4).


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  		Table 4. Pharmacokinetic parameters in patients in whom steroids were continued or discontinued at month 12

 
The inter-individual coefficient of variation was higher for C0/ND than for C2/ND at 3 months (P<0.05) and at 12 months (P<0.01) (Table 2). In terms of intra-individual stability of the dose–blood level relationship, the change from month 3 to month 12 was –16±31% for C0/ND and +9±55% for C2/ND. Intra-individual stability was even more limited for the relationship between C2 and C0 (C2/C0 ratio), which increased from month 3 to month 12 by 39±68%.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
This longitudinal analysis is the first to assess CsA pharmacokinetic parameters in both the de novo and maintenance phases for the same renal transplant patients.

Our results confirmed that CsA-ME bioavailability increases over the first 3 months post-transplant in a larger population than has previously been studied, and for the first time in patients receiving a third immunosuppressive agent (mostly mycophenolate mofetil). A substantial initial increase in bioavailability over the first few weeks post-transplant has previously been observed in renal transplant recipients receiving a dual regimen [6,15]. A Canadian study reported that CsA pharmacokinetic characteristics vary widely during the first 2 weeks post-transplant, becoming more stable and homogeneous by day 14 [15]. Subsequently, a prospective international trial found that the time to maximal concentration of CsA declined from 1.94 h at day 3 to 1.52 h at day 84 post-transplant [7]. Several factors may contribute to these changes, including recovery from post-operative gastroparesis, and co-medications that may influence the activity of intestinal P-glycoprotein and/or metabolizing enzymes.

Between months 3 and 12, the relationship between C2 level and CsA-ME dose remained generally stable. Unexpectedly, however, the decrease of C0 between months 3 and 12 was significantly more pronounced than the decrease in dose, such that the ratio of C0 to normalized CsA-ME dose declined by 22% on average, with a corresponding increase in the C2/C0 relationship. As a result, CsA exposure may be higher at month 12 than month 3 despite a similar C0 value. This can be explained by an acceleration in CsA cytochrome P4503A4 complex. Cytochrome P4503A4 is thought to be the most important factor in determining the rate of CsA metabolism after the first weeks post-transplant in renal transplant patients receiving a calcineurin inhibitor [16]. Recently, a significant increase in intestinal CYP3A4 clearance of CsA over time that may, in part, be due to heightened activity of the enzyme, was demonstrated in CsA-treated patients that was not apparent with sirolimus or tacrolimus [17]. If CsA clearance accelerates over time to a clinically relevant extent, one would expect this to be apparent in both C2/dose and C0/dose. However, in this population of patients from the MO2ART study, we only saw this reflected in the C0/dose relationship.

We assessed several patient subgroups (elderly, females, patients with DGF), none of which appeared to have a distinctly different pharmacokinetic profile, although minor variations may not have been detected due to relatively low numbers in the subpopulations and interpatient variability. It has been postulated that diabetic patients have impaired CsA absorption [18], but within our small population of diabetics (n = 5) this was not apparent. Patients who discontinued steroids prior to month 12 appeared to have a higher absorption at month 12 compared with those who were maintained on steroids, but the increase in elimination and metabolism between month 3 and month 12 was highly significant in both groups.

Finally, our results corroborate findings from a previous study in stable C0-monitored renal transplant patients which showed that more than half of patients had C2 levels above the upper target level, and that CsA dose reduction in these patients led to a decrease of serum creatinine [19]. Midtvedt et al. [20] subsequently reported that C2 monitoring of maintenance renal transplant patients may detect overexposure to CsA, specified in their study to be C2 level above 700–800 ng/ml [20]. Findings from the current study also indicated that the inter-patient coefficient of variation of dose-normalized C2 is significantly lower than for C0, at both 3 and 12 months post-transplant.

To date, the changes we observed in the ratio of C0 to weight-normalized dose of CsA-ME during months 3–12, which resulted in divergent patterns of C0/dose and C2/dose over time, have not been reported elsewhere. Further extended pharmacokinetic assessments are required to confirm our findings. We acknowledge the limitations of our investigation, in particular the small number of time points for which both C0 and C2 samples were available, which precluded calculation of area under the curve (AUC0–4) or an in-depth analysis of intra-individual variability. Neither do our dataset provide an explanation for the significant increase in C2/ND among patients who were steroid-free between months 3 to 12, while the ratio remained stable in patients receiving steroids. We can only speculate that this may have been due to investigators’ concern to maintain adequate immunosuppression in the absence of steroid therapy. However, it is interesting to note that Lemahieu et al. [21] recently reported a fall in CYP3A4 and PGP activity over time post-transplant, and proposed that the most plausible explanation was the concomitant tapering of steroid dose. Lastly, while we are aware that the CsA dose was adjusted based on C2 and not C0, we do not believe that this will have modified the C2/C0 ratio. The strengths of the analysis are the large and homogenous patient population, followed prospectively over the first year from time of transplant, the capacity to assess subpopulations, the use of a central laboratory to standardize CsA measurements, and the precisely timed assessments of pharmacokinetic parameters under study conditions.

In summary, we confirmed that CsA-ME absorption increases between the first week and month 3 post-transplant. Unexpectedly, our results indicated that CsA metabolism and elimination accelerates between month 3 and month 12, which may result in progressive underestimation of CsA exposure with C0 monitoring. We conclude that C2 monitoring is a valuable tool and can contribute to optimal individualized CsA treatment not only in the early post-transplant phase, but also throughout the first year post-transplant.

Conflict of interest statement. E. Cole, S. Chapman, K. Midtvedt and E. Thervet have received honoraria from Novartis for speaking at scientific meetings and received financial support for research activity. P. Keown holds research grants and contracts from Novartis, and has received honoraria from Novartis for speaking at scientific meetings. H. Prestele is an employee of Novartis Pharma AG.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Srinivas TR, Meier-Kriesche H-U, Kaplan B. Pharmacokinetic principles of immunosuppressive drugs. Am J Transplant 2005; 5: 207–217[CrossRef][Medline]
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  10. Einecke G, Mai I, Diekmann F, Fritsche L, Neumayer HH, Budde K. Cyclosporine absorption profiling and therapeutic drug monitoring using C(2) blood levels in stable renal allograft recipients. Transplant Proc 2002; 34: 1738–1739[Medline]
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Received for publication: 21. 4.05
Accepted in revised form: 8. 8.05


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