Experience with conversion from sandimmun to neoral cyclosporine and the correlation of c2 levels with renal function

Experience With Conversion From Sandimmun to Neoral Cyclosporine and the Correlation of C2 Levels With Renal Function I. Konstadinidou and J.N. Boletis ABSTRACT Pharmacologic monitoring of the cyclosporine microemulsion Neoral is an important tool to improve the efficacy and to avoid toxicity of the drug. Recent trials have shown that the absorption profiling tools represented by the area under the time-concentration curve from 0 to 4 hours postdose and concentration 2 hours postdose (C2) levels are the best predictors of acute rejection in the early posttransplant period. Since similar data regarding maintenance immunosuppression are scarce, we report our experience on Neoral C2 monitoring in renal transplant recipients during the late posttransplant period. However, available data on optimal Neoral C2 levels in the late posttransplantation period are scant and have not been correlated with well-defined endpoints such as chronic allograft nephropathy.

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INCE THE MID-1980s, cyclosporine (CsA; Sandimmun) in an olive- (liquid) or corn oil- (gel cap) based product, has been the principal immunosuppressive agent for induction and maintenance treatment in organ transplantation.1 Neoral, Since 1994 the oral formulation, of CsA is a microemulsion preconcentrate–Neoral—which contains mixture of corn oil, surfactant, and cosurfactant. This formulation was developed to overcome the high intraand interindividual variability in absorption of the standard oil-based formulation Sandimmun. Clinical trials in renal and liver transplant recipients have shown that the bioavailability of Neoral is improved; namely, a faster, more extensive, and more predictable absorption after oral ingestion. Neoral is a “critical dose drug,” which requires CsA exposure control for successful treatment.2– 6 PHARMACOKINETIC CYCLOSPORINE (NEORAL) PROFILES

The highest degree of inter- and intraindividual variability in CsA blood concentrations occurs during the absorption phase (the first 4 hours postdose) with minimal variability from 4 to 12 hours postdose. This narrowing of the “zone of pharmacokinetic variability” to the absorption phase may explain why absorption profiling tools (C2 ⫽ the concentration 2 hours postdose and AUC0 – 4 ⫽ the area under the time-concentration curve from 0 to 4 hours postdose) have made a significant contribution to improving clinical endpoints. A variability analysis of two separate pharmacokinetic profile data sets from renal and cardiac transplant recipients demonstrated that the absorption phase of CsA © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 163S⫺166S (2004)

from the microemulsion formulation exhibited the greatest degree of intra- and interpatient variability.7– 40 One study41 retrospectively examined the relationship between AUC4 during the first 3 to 5 days posttransplant and subsequent acute rejection episodes in renal transplant recipients. The relationship between the incidence of serum creatinine elevations (that may be due to CsA) and AUC4 was also examined. The study population included 156 consecutive first renal transplant recipients who received CsA-based immunosuppressive therapy with the microemulsion formulation, which was initiated at doses of 8 to 10 mg/kg/d and adjusted to keep C0 in the target range of 0.25 to 0.40 ␮g/mL (whole blood) during the first month after transplantation. C0 correlated poorly with AUC4 and AUC12. Furthermore the mean C0 was not significantly different among patients with or without acute rejection episodes (0.293 ⫽ 0.021 vs 0.294 ⫽ 0.011 ␮g/mL, respectively, P ⫽ .95). The poor predictability of C0 was further substantiated by the observation that 44% of the study patients with therapeutic C0 values experienced an acute rejection episode. Mean AUC4 values were significantly lower among patients with versus without acute rejection (3.934 ⫾ 0.306 vs 4.802 ⫾ 0.166 ␮g/mL · h, P ⫽ .006). When From the Department of Nephrology and Transplant Center, Laiko Hospital, Athens, Greece. Address reprint requests to Dr John N. Boletis, MD, PhD, Nephrologist, Director of the Transplant Center, Laiko Hospital, 17 St Thoma S, GR-115 27 Athens, Greece. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.01.040 163S

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Fig 1.

Laiko Hospital, Athens.

patients were stratified into three groups based on the range of AUC4 values (⬍4.4, 4.4 to 5.5, and ⬎5.5 ␮g/ml · h), the cohort in the middle range exhibited the lowest incidence of acute rejection. Routine renal biopsies at 6 to 9 months transplant led to the diagnosis of subclinical rejection in 18% of patients. The mean C2 was significantly lower in this group at the time of biopsy (C2 ⫽ 1 ␮g/mL) compared with the group without evidence of subclinical rejection (C2 ⫽ 1.2 ␮g/mL whole blood; mRIA, P ⫽ .04). There was no difference between the mean C0 for the group with or without subclinical rejection. This study confirms the greater sensitivity of C2 versus C0 monitoring as an indicator of clinical effects of CsA therapy in renal transplant patients.42–52 THE EXPERIENCE IN THE TRANSPLANT CENTER OF LAIKO HOSPITAL

We sought to examine the long-term impact of C2 on graft function (Fig 1) to optimize the use of Neoral in maintenance immunosuppression, bearing in mind that Neoral was substituted for Sandimmun since June 1995, and C2 levels (whole blood, mRIA Instar by Sorin), since 1998. In an initial study we reviewed the outcome of conversion of renal transplant patients from Sandimmun to Neoral to confirm the safety of the new formulation and its pharmacokinetic advantages.53 One hundred fifty randomly selected renal transplant recipients with stable renal function (mean serum creatinine ⫾ SEM ⫽ 1.7 ⫾ 0.5 mg/dL) were converted on a 1:1 dosing ratio from Sandimmun oral solution to Neoral soft gelatin capsules. The dose of Neoral was adjusted to maintain the same trough levels of CsA.

Serum creatinine, 12-hour CsA trough levels, uric acid, liver enzymes, and blood pressure were measured at baseline and at 1, 3, 6, 12, 18, and 24 months after conversion. Following transfer to Neoral, 231 dose changes were required in 123 patients (82%), mostly in response to CsA levels or in a few cases to renal dysfunction. In 133 cases (58%) the Neoral dose was decreased, while in 98 it was increased (42%). The reduction in the mean daily dose was about 2.4% at 12 months and 4.6% at 24 months. When the patients were transferred to Neoral from Sandimmun, a significant difference was noted in the mean CsA trough levels (145 ⫾ 35 ng/mL vs 132 ⫾ 3 ng/mL, P ⬍ .01). The mean serum creatinine remained stable up to month 24, although at month 12, it was slightly decreased (1.67 ⫾ 0.04 vs 1.69 ⫾ 0.53 mg/dL, P ⬍ .01). There was no difference in blood pressure or in the use of antihypertensive agents. During the 24 month follow-up there were no episodes of acute rejection, and none of the other laboratory parameters or blood pressure values changed. Therefore, we concluded that the use of Neoral in stable renal transplant recipients previously on Sandimmun is safe and advantageous. The improved bioavailability of the microemulsion formulation of CsA led to the use of significantly lower doses of Neoral. Subsequently, we retrospectively evaluated graft function in relation to C2 levels while patients were on maintenance immunosuppression with Neoral.54 One hundred sixty-nine renal transplant recipients (102 men and 67 women) who had stable renal function (mean serum creatinine ⫾ SEM ⫽ 1.8 ⫾ 0.1 mg/dL), at 6.5 ⫾ 0.2 years posttransplantation on CsA (3.0 ⫾ 0.1 mg/kg/d) in combination with AZA (68.9 ⫾

CONVERSION FROM SANDIMMUN TO NEORAL

1.9 mg/d) and methylprednisolone (4.8 ⫾ 0.3 mg/d). The mean CsA trough levels were 153 ⫾ 3 ng/mL and the 2-hour levels were 683 ⫾ 14 ng/mL were divided into three groups according to C2 levels: ⬍600 ng/mL (range 300 to 595 ng/mL), 600 to 900 ng/mL, and ⬎900 ng/mL (range 910 to 1130 ng/mL). No patient had changed the immunosuppressive regimen since transplantation; all had a minimum of 3 years follow-up on Neoral. An increase in serum creatinine by 1 mg/dL or ⱖ50% from the first year posttransplant measurement was deemed to be an adverse outcome. No differences were observed in serum creatinine; or the doses of CsA, methylprednisolone, or azathiopline (AZA) among the three groups. There was a significant difference in the mean time posttransplant among the C2 groups. The percentage of patients with reduction in graft function was significantly different among the three groups; the lowest being in the group with C2 ⬎ 900 group ng/mL (median 950 ng/mL) (P ⬍ .001). It has to be stressed that C2 levels higher than 900 ng/mL were associated with the least decline in graft function within the first 4 years posttransplantation. However, no differences were noted among the three C2 groups an graft loss 7.1% vs 9.3% vs 10%, P ⫽ NS). In this study using a mean Neoral dose of 3.0 mg/kg/d, C2 levels correlated with C0 levels and with CsA dose. Linearregression analyses showed significant correlations between C2 levels, CsA dose, and trough levels. In conclusion, the results of this analysis suggest that in Neoral-treated renal transplant patients graft function seems to be adequately preserved with C2 levels ⬎900 ng/mL (median 950 ng/mL, range 910 to 1130 ng/mL), especially within the first 4 years posttransplantation. An attempt was made to evaluate graft function in relation to C2 levels among Neoral-treated renal transplant recipients on AZA (n ⫽ 55) versus mycophenolate mofetil (MMF) (n ⫽ 45).55 All patients had stable renal function on maintenance immunosuppression with either AZA (mean ⫾ SEM dose ⫽ 1.04 ⫾ 0.05 mg/kg/d) or MMF (mean dose ⫽ 1.88 ⫾ 0.04 g/d) in combination with CsA and methylprednisolone. All patients had been on the same immunosuppressive regimen since transplantation and were on Neoral for at least 3 years. Again, the patients were divided in three subgroups according to their C2 levels: ⬍600 ng/mL (range 265 to 590 ng/mL), 600 to 900 ng/mL, and ⬎900 ng/mL (range 905 to 1170 ng/mL), and an increase in serum creatinine by 1 mg/dL or by ⱖ50% from the first year posttransplant measurement was considered to be graft dysfunction. No differences were observed in the doses of CsA (3.4 ⫾ 0.1 mg/kg/d in the AZA group vs 3.2 ⫾ 0.1 mg/kg/d in the MMF group, P ⫽ NS) or methylprednisolone (4.5 ⫾ 0.1 mg/d vs 4.5 ⫾ 0.3 mg/d, respectively, P ⫽ NS), or in the percentage of hypertensive patients (65.3% vs 63.1%, respectively, P ⫽ NS), or in systolic or diastolic blood pressures between the two groups (mean systolic: 145 ⫾ 15 mm Hg vs 132 ⫾ 3 mm Hg, P ⫽ NS, mean diastolic: 84 ⫾ 1 vs 84 ⫾ 2 mm Hg, respectively, P ⫽ NS). The percentages of patients with an increase in serum creatinine by 1 mg/dL or by ⱖ 50% from the first year posttransplant

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measurement were grouped according to C2 levels. Among the patients taking AZA, these with C2 ⬎ 900 ng/mL (mean 958 ⫾ 5 ng/mL, range 905 to 1170 ng/mL) had the lowest prevalence of graft dysfunction (10.0% vs 40.0%, RR 0.167, 95% CI 0.107 to 2.064, P ⫽ .05), while those on MMF showed the lowest prevalence with C2 levels 600 to 900 ng/mL (mean 769 ⫾ 14 ng/mL), atleast albeit a difference that did not reach statistical significant (9.7% vs 3.1%, RR 3.320, 95% CI 0.034 to 28.170, P ⫽ NS). In conclusion, absorption and bioavailability of CsA are important for clinical outcomes and the AUC0 – 4 predictor is represented reliably by C2 levels. During the early posttransplant period desirable Neoral C2 levels can be established with relative accuracy, since the evaluation endpoints (acute rejection or acute CsA toxicity) are well defined. Although some reports are available on Neoral C2 levels in the late posttransplantation period, studies with well-defined endpoints (eg, chronic allograft nephropathy) are still lacking. REFERENCES 1. Opelz G, Do ¨hler B: Transplantation 72:1267, 2001 2. Holt DW, Johnston A: J Autoimmun 5(Suppl A):177, 1992 3. Johnston A, Holt DW: Clin Pharmacokinet 28:93, 1995 4. Johnston A, Holt DW: Br J Clin Pharmacol 52(Suppl 1):61S, 2001 5. Shah MB, Martin JE, Schroeder TJ, et al: Transplantation 67:1411, 1999 6. Cahan B, Kelly P: Immunosuppressive drugs: pharmacology. In Kahan B, Ponticelli C (eds), Principles and Practice of Renal Transplantation; Martin Dunitz Ltd: London, UK, 2000, p 251 7. Johnston A, Kovarik JM, Mueller EA, et al: Transpl Int 9(Suppl 1):S305, 1996 8. David O, Johnston A: Limited sampling strategies. Clin Pharmacokinet 39:311, 2000 9. David OJ, Johnston A: Ther Drug Monit 23:100, 2001 10. Lindholm A, Welsh M, Alton C, et al: Clin Pharmacol Ther 52:359, 1992 11. Johnston A, Kovarik JM, Mueller EA, et al: Transpl Int 9(Suppl 1):S305, 1996 12. Cantarovich M, Besner JG, Fitchett DH, et al: Clin Transplant 11(5 Pt 1):399, 1997 13. Keown P, Kahan BD, Johnston A, et al: Transplant Proc 30:1645, 1998 14. Belitsky P, Mahalati K, West K, et al: Transplant Proc 31:1667, 1999 15. Malahati K, Belitsky P, Sketris I, et al: Transplantation 68:55, 1999 16. Keown PA: Transplant Proc 31:1790, 1999 17. Mahalati K, Bellitsky P, Sketris I, et al: Transplantation 68:55, 1999 18. Grand D, Kneteman N, Tchervenkov J, et al: Transplantation 67:1133, 1999 19. Kelles A, Herman J, Tjandra-Maga TB, et al: Pediatr Transplant 3:282, 1999 20. Halloran P, Helms L, Kung L, et al: Transplantation 68: 1356, 1999 21. Johnston A, David OJ, Cooney GF: Transplant Proc 32(3A Suppl):53S, 2000 22. Holt DW, Johnston A: Transplant Proc 32:1552, 2000 23. Sinhi R, Lavia MF, Paulling E, et al: Transplantation 69:432, 2000 24. Cole EH: Transplant Proc 32:1556, 2000 25. Levy G: Biodrugs 15:279, 2001

166S 26. Mahalati K, Belitsky P, West K, et al: J Am Soc Nephrol 12:828, 2001 27. Mahalati K, et al: JASN 12:826, 2001 28. Johnston A, Holt DW: Br J Clin Pharmacol 52(Suppl 1):61S, 2001 29. Dunn CJ, Wagstaff AJ, Perry CM, et al: Drugs 61:1957, 2001 30. Dunn S, Falkenstein K, Cooney G: Transplant Proc 33:3094, 2001 31. Keown P: Transplantation 72(Suppl 12):SS67, 2001 32. Keown PA: Curr Opin Nephrol Hypertens 11:619, 2002 33. Levy G, Burra P, Cavallari A, et al: Transplantation 73:953, 2002 34. Levy G, Thervet E, Lake J, et al: Transplantation 73(Suppl 9):S12, 2002 35. International Neoral Renal Transplantation Study Group: Am J Transplant 2:146, 2002 36. Nashan B, Cole E, Levy G, et al: Transplantation 73(Suppl 9):S3, 2002 37. Thervet E, Pfeffer P, Scolari MP, et al: Transplantation 76:903, 2003 38. Holt DW, Marsden JT, Johnston A, et al: Br Med J (Clin Res Ed) 293:1057, 1986 39. Grant D, Rochon J, Levy G: Transplant Proc 28:2232, 1996 40. Grand D, Kneteman N, Tchervenkov J, et al: Transplantation 67:1113, 1999 41. Belitsky P, Dunn S, Johnston A, et al: Clin Pharmacokinet 39:117, 2000

KONSTADINIDOU AND BOLETIS 42. Belitsky P, Levy GA, Johnston A: Transplant Proc 32(Suppl 3A):45S, 2000 43. Holt DW, Johnston A, Kahan BD, et al: Clin Chem 46:872, 2000 44. Johnston A, David OJ, Cooney GF: Transplant Proc 32(Suppl 3A):53S, 2000 45. Cooney GF, Johnston A: Transplant Proc 33:1572, 2001 46. Banner NR, David OJ, Leaver N, et al: Transpl Int 15:649, 2002 47. Cole E, Midtvedt K, Johnston A, et al: Transplantation 73(Suppl 9):S19, 2002 48. Kahan BD, Keown P, Levy GA, et al: Clin Ther 24:330, 2002 49. Pescovitz MD, Barbeito R: Clin Transplant 16:378, 2002 50. Cantarovich M, Giannetti N, Cecere R: Clin Transplant 17:144, 2003 51. Johnston A, Chusney G, Schutz E, et al: Ther Drug Monit 25:167, 2003 52. Trompeter R, Fitzpatrick M, Hutchinson C, et al. Pediatr Transplant 7:282, 2003 53. Boletis JN, Konstadinidou I, Stamatiadis D, et al: Proceedings of the Third Congress of BANTAO (Balkan Cities Association of Neprhology, Dialysis, Transplantation and Artificial Organs). Medical Investigations 33:124, 1999 54. Konstadinidou I, Avdikou K, Hiras Th, et al: 10th Congress of ESOT, Lisboa (Portugal) 293, 2001 55. Konstadinidou I, Stamataki E, Filiopoulos V, et al: 8th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology, Basel (Switzerland) TDM-I 54, 2003