HM Medical Clinic

 

08. bƒlent yÜÚÜt 177-180

A comparison of C0 and C2 monitoring in
renal transplant patients
Bülent Yi¤it*, Melih Kara, ‹brahim Berber, Gürkan Tellio¤lu, Funda Türkmen, ‹zzet Titiz
Haydarpafla Numune Research and Educational Hospital, Renal Transplantation Unit, ‹stanbul, Turkey Objectives: To compare the effects of Cyclosporine CsA-0 (C0) and CsA-2 (C2) level monitoring
on acute rejection (AR) and infection rates, toxicity and graft survival in patients with renal trans-
plantation.
Methods: Prospectively evaluated 10 patients with C2 monitoring (group C2) were compared
to a group of 10 patients with C0 monitoring (group C0). In C2 group C0 levels were also
recorded but drug doses were adjusted according to C2 levels. CsA doses, C0 and C2 blood lev-
els , Glomerular Filtration Rate (GFR), were analyzed in 3 time periods (≤ 1 month, >1- ≤3
months , >3- ≤6 months ) post transplantation.
Results: Two groups were similar in mean age, sex, donor type and antilymphocyte treatment.
Delayed graft function was seen in 1 patient in group C0. All patients had at least 3 months fol-
low up. CsA beginning dose was 8 mg/kg/day in all patients. Adjusted drug doses of patients
in group C2 were higher than the doses in group C 0 in all time periods; the difference was
significant between the two groups only in the first month (6.34 mg/kg and 4.47 mg/kg respec-
tively in C2 and C0) (p < 0.05). Although CsA-0 level is always higher in C2 group, the differ-
ences of CsA-0 levels are not statistically significant in the 1st 3rd 6th months in both groups.
Differences in GFR was higher in group C2 and it was significantly higher only in the first peri-
od (p < 0.05). Transient nephrotoxicity was seen in 1 patient in each group .Acute rejection was
seen in 3 patients, 2 in group C0 and in group C2 and although these values are not statistically
significant their Banf score is different and more severe rejection is seen in C0 monitoring
Conclusion: C2 monitoring results in better graft function with similar adverse effects when
compared to C0 monitoring in renal transplant patients.Although the incidence of AR rates sim-
ilar in each group,rejection is histologically more severe in C0 group compared to C2 group.The
efficacy and severity of altered dosing regimen based on C2 were good and provided clinical
benefits by reducing the severity of AR.
Key words: Acute rejection, CsA-0, CsA-2 level renal transiplant
Adv Mol Med 2005; 1(4): 177-180 (Neoral),drug monitoring guidelines,and the emerging Cyclosporine (CsA) is the cornerstone of immuno- role of CsA-based combination therapies.1 Traditional supression in renal transplant recipients. By binding to monitoring was by measuring the through (CsA-0) (C0) immunophilins, they inhibit the phosphatese cal- *Correspondence to: Bülent Yi¤it, MD cineurin which is essential in the signal transduction Haydarpafla Numune Research and Educational Hospital, pathway that ultimately leads to transcription of the Renal Transplantation Unit, ‹stanbul, Turkey.
gene for IL-2. Although CsA has been introduced into Phone: +90 216 414 45 02 - 1385Fax: +90 216 567 45 59 clinical transplantation nearly for 20 years, there have been significant advances in the formulation design Accepted: November 12, 2005 2005 DEOMED
level 12 hours after an oral dose, but soon it was unter- Mean age are similar, 28.2±9.34 and 32.8±9.65 in C0 stood that CO level does not correlate well with drug group and C2 group resepectively. Male/female ratio is exposure as measured by area under the concentration- 6/4 in both groups and donor type is also similar in time curve (AUC), based on 12-hr pharmacokinetic both groups.
analysis (AUC 0-12) (2 levy) and does not predict free- CsA doses in both groups are given in Table 2. CsA dom from rejection.2 The absorbtion phase for Neoral beginning dose was 8 mg/kg/day in all patients.
occurs usually within 2-hr after administration of the Adjusted drug doses of patients in group C2 were high- drug,3 characterized by rapid rise in blood CsA con- er than doses in group C0 in all time periods. The dif- centration. Recent studies have demonstrated that mon- ferences were significant in the first month (p<0.05), itoring strategies to estimate AUC or CsA levels 2-hr but not significant in the 3rd and 6th month (p=0.9 and after dosing CsA-2 (C2) may be more effective methods p=0.15 respectively). of optimizing CsA immunosupression.2 The aim of theour study to compare the effects of C0 and C2 level CsA doses given to C0 and C2 groups monitoring on acute rejection (AR), toxicity, infectionand graft survival in renal transplant patients.
CsA doses
CsA -0 group
CsA-2 group
Between 2001-2004 20 renal transplant patints were monitorized using C0 (10 patients) and C2 (10 patients)level. Mean age of patients in C0 group were 28.2±9.34and C2 group were 32.8±9.65 male female ratio 6/4.for C0 levels were similar in the both groups in all time both groups.Patients were treated with CsA based triple periods. CsA-0 levels are given in table 3. Although immunosupressive regimen (mycophenatil mofelat CsA-0 level is always higher in C2 group, the differ- (1500-2000 mg) and corticosteroid). In C0 group ences of CsA-0 levels are not significant in the 1st 3rd 6th patients were dosed according to predicted C0 level months in both groups (p=0.117, p=0.120, p=0.189 inthe1st, 3rd, 6th months respectively).
(250-400 ng/ml for 1. month, 250-300 ng/ml for 1-3months and 200-250 for 3-6 months) and in C2 group were dosed to predicted C2 level (1700 ng/ml for 1.
CsA-0 levels in C0 and C2 groups month, 1300 ng/ml 1 and 3. months, 1100 ng/ml for 3-6. months). The primary efficacy endpoints were acute CsA-0 level
rejection, CsA doses, renal functions and drug toxicity.
CsA -0 group
CsA-2 group
Statistical analyses were performed using SPSS 9.0 for windows version including the ChiSquare and Student T test.
CsA-2 levels are given in Table 4. Our aim was to adjust C2 level as 1700 ng/ml for the 1st month, 1300 Mean age, sex and, donor type are given in Table 1.
ng/ml for the 3rd month and 1100 ng/ml for the 6thmonth and we reached our goal as seen in Table 4.
Glomerular filitration rate (GFR) is given in Table 5.
Mean age, sex and, donor type GFR is higher in C2 group in all three time periods butthe difference is statistically significantly higher only in CsA-0 group
CsA-2 group
the 1st month (p<0.05).
Sex (M/F)
Transient nephrotoxicity was seen in 1 patient in each group so it is not statistically significant between the two groups.
Adv Mol Med 2005; 1(4)
A comparison of C0 and C2 monitoring in renal transplant patients sure (AUC) and intrapatient variability in AUC, con- CsA-2 levels in C2 group tribute to a patient's clinical outcomes, such as inci-dence and severity of acute and chronic rejections.1 CsA-2 level (mean)
ng/ml (mean)
Most patients undergoing kidney transplantation before 1994 received the conventional cyclosporine formula- tion Sandimmune. From 1994, the new microemulsion formulation Neoral was available.6 Traditional monitor-ing was by measuring the through level taken 12 hours Totally acute rejection (AR) was seen in 3 patients, after an oral dose, but the results correlated poorly with 2 in C0 and 1 in C2, in all periods as given in Table 6 drug dose, toxicity and outcome. Pharmacokinetic stud- and the differance is not statistically significant but ies have shown Neoral to have more consistent and according to Banf score, AR in C0 is more severe than reliable absorption profile, with lower intra-patient the AR in C2 group variability and improved dose linearity with drug expo-sure, measured as AUC.2,7 The absorption phase forNeoral ocurs usually within 2 hours after administration Glomerular filitration rate in C0 and C2 groups of the drug, characterized by a rapide rise in blood CsAconcentrations and high degree of inter-patient vari- GFR (mean) (ml/min)
CsA-0 group
CsA2 group
ability.2 CsA monitoring tools Very recently, data have become available from prospective clinical trials that support application of a new method to monitor CsA levels. This new type of monitoring, called C2 monitor-ing, has been shown to improve outcomes in transplantpatients receiving CsA (Neoral) based immunosupres- sion.8-10 Drug exposure (AUC) was found to be a very Cyclosporine forms the cornerstone of immunosu- sensitive predictor of acute rejection incidence and pressive therapy in transplant recipients and its use graft survival at 1 year following renal transplantation.
continues to expand globally. One of the challanges in The University of Cincinati Renal Transplant group con- CsA management is the narrow therapeutic index that firmed the correlation between clinical outcomes and allows adequate T-cell immunosupression with mini- AUC in a seperate study. In both studies, the tradition- mum risk of adverse effects.4 Cyclosporine is a critical al monitoring approach that utilized C0 CsA blood con- dose drug with a narrow therapeutic index and requires centrations was a significantly less sensitive tool for monitoring through blood levels to avoid rejection optimisation of CsA immunosupression.11 The recom- through underexposure or toxicity through overexpo- mended target C2 levels is to identify the Neoral dose sure.5 CsA pharmokinetics, particularly systemic expo- required to maximise clinical outcome 1.7 µg/ml for 0 AcuteRejection in CO and C2 groups in three periods Acute rejection (+)
Acute rejection (–)
CsA-0 (n: 10)1 (10) 9 (90) (≤ 1 month)CsA-2 (n:10) CsA -0 (n: 10)1 (10) 9 (90) (> 1 - ≤ 3 month)CsA-2 (n:10) (> 3 - ≤ 6 month)CsA-2 (n: 10) CsA-0 (n:10)2 (20)8 (80) CsA-2 (n: 10)1 (10) 9 (90) Adv Mol Med 2005; 1(4)
to 6 months12 and 1.2 µg/ml for 6 to 12 months.13 C2 4. Kahan BD. Cyclosporine. N Engl J Med 1989; 321: 1725-38.
level monitoring has been proven to be a more effec- Pollard SG. Pharmacologic monitoring and outcomes of tive method to optimise clinical outcomes in renal cyclosporine. Transplant Proc 2004; 36: 404S-7S.
6. Opelz G, Dohler B. Cyclosporine and long term kidney graft sur- transplant recipients.2,8,12,-15 vival. Transplantation 2001; 72: 1267-73.
Our study showed that CsA doses are statistically 7. Muller EA, Kovarik JM, van Bree JB, et al. Improved dose linear- significantly higher in C2 group only in the first month, ity of cyclosporine Pharmacokinetics from a microemulsion for- CsA 0 levels in C0 and C2 groups are similar, not sta- mulation. Pharm Res 1994; 11(2): 301.
tistically significant, GFR is similar in the two groups C0 8. Mahalati K, Belistky P, Kiberd B, et al. Absorbtion profiling- a novel method for monitoring Neoral in Kidney transplantation and C2, transient nephrotoxicity was same in the two that reduces rejection and nephrotoxicity. Transplantation 2000; groups. Totally AR was seen in 3 patients, 2 in C0 and 69: S114, Abstract 12.
1 in C2. Although the incidence of AR was similar 9. Levy GA, Lake JR, Beauregard-Zollinger L, et al. Improved clini- between the two groups, histologically proven moder- cal outcomes for liver transplant recipients using cyclosporineblood level monitoring based on two hour post dose levels.
ate to severe AR was observed in the C2 group com- Transplantation 2000; 69: S387, Abstract 1059.
pared to C 0 group. Thus, the efficacy and safety of the 10. Cantarovich M, Besner J-G, Barkun JS, et al. Two hour altered dosing regimen based on C2 were good and cyclosporine level determination is the appropriprate tool to provided clinical benefits by reducing the severity of monitor Neoral therapy. Clin Transplant 1999; 12: 243-9.
acute rejection. More patients are needed for futher 11. Schroeder TJ, Hariharan S, First MR. Variations in Bioavailability of cyclosporine and relationship to clinical outcome in renaltransplant subpopulations. Transplant Proc 1995; 27: 837-9.
12. Mahalati K, Belistky P, Skretis I, et al. Neoral monitoring by sim- plified sparse sampling area under the concentration-time curve.
Transplantation 1999; 68: 55-62.
1. Belisty P. Neoral Use in the Renal Transplant Recipient.
Transplant Proc 2000; 32: 10S-9S.
13. Barama AA,Y›lmaz S, Gough J, et al. Lower cyclosporine expo- sure increases the risk for sub-clinical rejection in renal trans- 2. Levy G, Burra P, Cavallari A, et al. Improved clinical outcomes plant recipients. Transplantation 2000; 69: S225, Abstract 431.
for liver transplant recipients using cyclosporine monitoringbased on 2hours post dose levels (C2). Transplantation 2002; 73: 14. Thervet E, Pfeffer P, Scolari MP, et al. Clinical outcomes during the first three months posttransplant in renal allograft recipients 3. Grant D, Knetman N, Tchervenkov J, et al. Peak cyclosporine lev- managed by C2 monitoring of cyclosporine microemulsion.
Transplantation 2003; 76: 903-8.
max) correlate with freedom from liver graft rejection: results of a prospective , randomised comparison of Neoral and 15. Pescovitz MD, Barbeito R. Two-hour post-dose cyclosporine level Sandimmune for liver transplantation (NOF-8). Transplantation is a better predictor than trough level of acute rejection of renal 1999; 67(8): 1133.
allografts. Clin Transplant 2002; 16(5): 378-82.
Adv Mol Med 2005; 1(4)

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