- Email: [email protected]
A two-year study of the new cyclosporine formulation consupren in De Novo Renal transplant patients
A Two-Year Study of the New Cyclosporine Formulation Consupren in De Novo Renal Transplant Patients A.G. Stephan, A. Barbari, M. Masri, G. Kamel, W. Barakat Khoury, A. Karam, J. Mokhbat, and H. Kilany
W
RESULTS
CyA formulation, Neoral, because of what was considered “unsatisfactory” CyA kinetics. Conversion criteria included one or more of the following unstable CyA pharmacokinetic parameters: 1. maximum blood concentration (Cmax) less than 400 ng/mL; 2. time to maximum blood concentration (Tmax) delayed for more than 3 hours; 3. broad area under the curve (AUC); 4. fluctuating blood trough level (BTL); and 5. ratio of Cmax/BTL below 3. The new formulation dose was adjusted thus: 1. to maintain a BTL of about 50 ng/mL; 2. if Cmax was above 1200 ng/mL; and/or 3. there was more than a 20% increase in serum creatinine (Scr).1,2 The number of early rejection episodes was not unduly elevated (31%), and could be easily reversed with steroids. The suspected or biopsy-proven episodes of nephrotoxicity amounted to only 9% (1 biopsy-proven, 2 presumed). A total of 13 patients had postoperative infections; 6 were thought to be viral in origin (CMV) and 7 were bacterial. The bacterial infections were 5 UTI and 2 wound infections. Two additional patients had oral candidiasis. The length of follow-up varied from 18 to 30 months. The extrarenal side effects as shown in our previous report3 were not more frequent than with SIM.4 – 6
Results of our study are summarized in Tables 1 through 4. As shown, all patients experienced an immediate dieresis with precipitous drops in serum creatinine that stabilized at the accepted norms (average: 1.19 mg/dL). Of the 32 patients, 3 were later converted to another new
From Rizk Hospital, Beirut, Lebanon. Address reprint requests to Antoine Stephan, MD, Transplant Unit, Rizk Hospital, PO Box 11-3288, Beirut, Lebanon.
E have shown in a previous study that converting renal transplant recipients from regular Sandimmun (SIM) to the new cyclosporine A (CyA) formulation Consupren (CON) could be achieved safely with preservation of a good graft function, no added renal or extrarenal toxicity, and with significant cost benefits. The present study extends the use of CON as a primary immunosuppressant drug utilized de novo in the immediate posttransplant period.
MATERIALS AND METHODS The study included 32 patients (21 males, 11 females). Of the male patients, 10 received living unrelated kidneys (LUR), 9 received living related kidneys (LR), and 2 had cadaveric kidneys (CAD). Among the 11 female patients, 5 were transplanted from LUR kidneys and 6 from LR. All non-HLA-identical patients (except the 2 CAD recipients) were prepared with donor-specific transfusions (DST) under CON immunosuppression. Our immunosuppression protocol involves induction with antithymocyte globulin (ATG), Solu-Medrol, and azathioprine, with CON added on the 3rd to 4th postoperative day according to graft function. The initial CON dose is roughly 8 mg/kg and is tailored from then on according to a set of abbreviated kinetics (T0, T1, T2, T3, T4, T6). The CyA levels are measured on whole blood, using the Abbot TDX monoclonal assay for the parent compound.
Table 1. Overall Results Regarding Dose and the Different CyA Parameters Measured Condition
Starting
1 Month
6 Months
Current
Dose (mg/kg) BTL (ng/mL) Cmax (ng/mL) Cmax Time (h) Scr (mg/dL) EI
7.70 6 0.84 170 6 105 940 6 292 1.44 6 0.50 1.21 6 0.23 139
6.85 6 1.37 296 6 82 1055 6 248 1.85 6 0.35 1.26 6 0.28 112
3.83 6 0.89* 151 6 45 811 6 215 1.89 6 0.87 1.21 6 0.21 137
3.37 6 0.68* 121 6 37 608 6 332 1.85 6 0.65 1.14 6 0.19 133
*Significant (P , .001).
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00136-1
Transplantation Proceedings, 30, 3563–3564 (1998)
3563
3564
STEPHAN, BARBARI, MASRI ET AL Table 2. Rejections
Table 4. Renal Toxicity
1 Episode
2 Episodes
3 Episodes
Total
Steroid
ATG
4 — 4 4
5 1 6 3
5 4 9 3
14 5 19 10
12 5 17 9
2 — 2 2
Presumed Biopsy Total Patients
Total rejections 5 10/32, 31%
DISCUSSION
In a previous paper we reported that CON offered a safe CyA formulation capable of maintaining good renal function in stable kidney transplant recipients previously controlled with SIM.3 Since then these reported patients have been followed for more than 2 years, with no obvious untoward effects. The present study was undertaken to verify that CON would be just as adequate when used de novo at a time when the tendency to reject is at its peak (ie, in the immediate posttransplant period).7 This is the time to use the most potent immunosuppressive regimens available. It is also during this crucial period that most of the complications are liable to occur.4,8 CON is nothing else but CyA provided with a new vehicle.9 –11 The mechanism of action of CyA has been thoroughly investigated. By binding with cyclophilin, CyA inhibits the calcium-dependent phosphatase calcineurin, which is necessary for the translocation of the cytoplasmic component of NFAT, to the nucleus. This step is essential for the transcription of the IL-2 gene.7,8 The suppression of IL-2, as well as a host of other lymphokines, is the basis of the unquestionable potent immunosuppressive effect of CyA. Unfortunately, no sensitive laboratory assays of CyA immunosuppression are as yet available.12,13 We have thus to keep relying on empirical clinical results and laboratory approximations that are necessarily fraught with all sorts of potential errors. It is for this reason that we have multiplied the use of the known parameters for CyA dosage (ie, Cmax, BTL, EI, kinetics, AUC).3,8 According to these parameters, CON has performed significantly better than SIM. As for the value of CON as an immunosuppressant, we had to rely exclusively on the clinical events associated with its use. With initial doses comparable to SIM, the function of the renal graft (as estimated by such crude parameters as Scr)14,15 looked satisfactory. The incidence of early rejection episodes was if anything Table 3. Side Effects EBV
Herpes
CMV
BP (130 –150)
BP (.150)
Tremor
0/32
3/32
7/32
6/32
3/32
7/32
Presumed
Biopsy
Total
1/32 (3%)
2/32 (6%)
3/32 (9%)
lower16 and their reversal with the usual course of SoluMedrol was as easy. No undue renal toxicity could be detected, and the incidence of the most common extrarenal toxic manifestations of CyA5,6,17 (ie, hypertension, hirsutism, gingival hypertrophy, and neurological problems) was in no way more frequent or more severe. In conclusion, the new CyA formulation offers a valid alternative to SIM. Using CON de novo in renal transplant recipients provides adequate immunosuppression, with no increase in untoward side effects. These conclusions are, however, always subject to the following unsolved shortcomings: 1. lack of adequate assessment of functioning renal mass; and 2. lack of a sensitive assessment of CyA dosage both regarding immunosuppression and toxicity. REFERENCES 1. Barbari A, Stephan A, Kamel G, et al: Transplant Proc (in press) 2. Masri MA, Barbari A, Stephan A, et al: Transplant Proc 28:1318, 1996 3. Stephan AG, Barbari A, Masri MA, et al: Transplant Proc 28:1348, 1996 4. Thiru S, Maher ER, Hamilton DV, et al: Transplant Proc 15:2846, 1983 5. Wysocki GP, Gretzinger HA, Lacipacis A, et al: Oral Surg 55:274, 1983 6. Kahan BD, Flechner SM, Lorber MJ, et al: World J Surg 10:348, 1986 7. Bach FH, Auchincloss HJ: Transplantation Immunology. New York: Wiley–Liss; 1995, pp 65–76, 95–102 8. Harjula A, Hockerstedt K: Atlas of Clinical Transplantation. Recall Medical Publishers; 1995, pp 25–56 9. Klima J, Mah I, et al: Archives of Clinical Department, Galena, 1989 10. Klima J, Mah I, et al: Proceedings of the First Symposium on Consupren (cyclosporin) 9, April 1991 11. Puretic Z: Institute for Clinical Pharmacology, Dept. of Internal Medicine, University Hospital Center, Zagreb 12. Faulds D, Karen L, Benfield GP: Drug 45(6):953, 1993 13. Akagi A, Reynolds A, Hjelm M: J International Med Res 19:1, 1991 14. Slomowitz LA, Wilkinson A, Hawkins R, et al: Am J Kidney Dis 15:530, 1990 15. Walser M, Drew HH, La France ND: Kidney Int 34:412, 1988 16. Taesh S, Niese D: Transpl Int 7(suppl 1):263, 1994 17. Marumo T, Nakaki T, Hishikawa K, et al: Hypertension (pt 2):764, 1995 18. Goerel J: Clin Pharmacokinet 23:380, 1992
W
RESULTS
CyA formulation, Neoral, because of what was considered “unsatisfactory” CyA kinetics. Conversion criteria included one or more of the following unstable CyA pharmacokinetic parameters: 1. maximum blood concentration (Cmax) less than 400 ng/mL; 2. time to maximum blood concentration (Tmax) delayed for more than 3 hours; 3. broad area under the curve (AUC); 4. fluctuating blood trough level (BTL); and 5. ratio of Cmax/BTL below 3. The new formulation dose was adjusted thus: 1. to maintain a BTL of about 50 ng/mL; 2. if Cmax was above 1200 ng/mL; and/or 3. there was more than a 20% increase in serum creatinine (Scr).1,2 The number of early rejection episodes was not unduly elevated (31%), and could be easily reversed with steroids. The suspected or biopsy-proven episodes of nephrotoxicity amounted to only 9% (1 biopsy-proven, 2 presumed). A total of 13 patients had postoperative infections; 6 were thought to be viral in origin (CMV) and 7 were bacterial. The bacterial infections were 5 UTI and 2 wound infections. Two additional patients had oral candidiasis. The length of follow-up varied from 18 to 30 months. The extrarenal side effects as shown in our previous report3 were not more frequent than with SIM.4 – 6
Results of our study are summarized in Tables 1 through 4. As shown, all patients experienced an immediate dieresis with precipitous drops in serum creatinine that stabilized at the accepted norms (average: 1.19 mg/dL). Of the 32 patients, 3 were later converted to another new
From Rizk Hospital, Beirut, Lebanon. Address reprint requests to Antoine Stephan, MD, Transplant Unit, Rizk Hospital, PO Box 11-3288, Beirut, Lebanon.
E have shown in a previous study that converting renal transplant recipients from regular Sandimmun (SIM) to the new cyclosporine A (CyA) formulation Consupren (CON) could be achieved safely with preservation of a good graft function, no added renal or extrarenal toxicity, and with significant cost benefits. The present study extends the use of CON as a primary immunosuppressant drug utilized de novo in the immediate posttransplant period.
MATERIALS AND METHODS The study included 32 patients (21 males, 11 females). Of the male patients, 10 received living unrelated kidneys (LUR), 9 received living related kidneys (LR), and 2 had cadaveric kidneys (CAD). Among the 11 female patients, 5 were transplanted from LUR kidneys and 6 from LR. All non-HLA-identical patients (except the 2 CAD recipients) were prepared with donor-specific transfusions (DST) under CON immunosuppression. Our immunosuppression protocol involves induction with antithymocyte globulin (ATG), Solu-Medrol, and azathioprine, with CON added on the 3rd to 4th postoperative day according to graft function. The initial CON dose is roughly 8 mg/kg and is tailored from then on according to a set of abbreviated kinetics (T0, T1, T2, T3, T4, T6). The CyA levels are measured on whole blood, using the Abbot TDX monoclonal assay for the parent compound.
Table 1. Overall Results Regarding Dose and the Different CyA Parameters Measured Condition
Starting
1 Month
6 Months
Current
Dose (mg/kg) BTL (ng/mL) Cmax (ng/mL) Cmax Time (h) Scr (mg/dL) EI
7.70 6 0.84 170 6 105 940 6 292 1.44 6 0.50 1.21 6 0.23 139
6.85 6 1.37 296 6 82 1055 6 248 1.85 6 0.35 1.26 6 0.28 112
3.83 6 0.89* 151 6 45 811 6 215 1.89 6 0.87 1.21 6 0.21 137
3.37 6 0.68* 121 6 37 608 6 332 1.85 6 0.65 1.14 6 0.19 133
*Significant (P , .001).
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00136-1
Transplantation Proceedings, 30, 3563–3564 (1998)
3563
3564
STEPHAN, BARBARI, MASRI ET AL Table 2. Rejections
Table 4. Renal Toxicity
1 Episode
2 Episodes
3 Episodes
Total
Steroid
ATG
4 — 4 4
5 1 6 3
5 4 9 3
14 5 19 10
12 5 17 9
2 — 2 2
Presumed Biopsy Total Patients
Total rejections 5 10/32, 31%
DISCUSSION
In a previous paper we reported that CON offered a safe CyA formulation capable of maintaining good renal function in stable kidney transplant recipients previously controlled with SIM.3 Since then these reported patients have been followed for more than 2 years, with no obvious untoward effects. The present study was undertaken to verify that CON would be just as adequate when used de novo at a time when the tendency to reject is at its peak (ie, in the immediate posttransplant period).7 This is the time to use the most potent immunosuppressive regimens available. It is also during this crucial period that most of the complications are liable to occur.4,8 CON is nothing else but CyA provided with a new vehicle.9 –11 The mechanism of action of CyA has been thoroughly investigated. By binding with cyclophilin, CyA inhibits the calcium-dependent phosphatase calcineurin, which is necessary for the translocation of the cytoplasmic component of NFAT, to the nucleus. This step is essential for the transcription of the IL-2 gene.7,8 The suppression of IL-2, as well as a host of other lymphokines, is the basis of the unquestionable potent immunosuppressive effect of CyA. Unfortunately, no sensitive laboratory assays of CyA immunosuppression are as yet available.12,13 We have thus to keep relying on empirical clinical results and laboratory approximations that are necessarily fraught with all sorts of potential errors. It is for this reason that we have multiplied the use of the known parameters for CyA dosage (ie, Cmax, BTL, EI, kinetics, AUC).3,8 According to these parameters, CON has performed significantly better than SIM. As for the value of CON as an immunosuppressant, we had to rely exclusively on the clinical events associated with its use. With initial doses comparable to SIM, the function of the renal graft (as estimated by such crude parameters as Scr)14,15 looked satisfactory. The incidence of early rejection episodes was if anything Table 3. Side Effects EBV
Herpes
CMV
BP (130 –150)
BP (.150)
Tremor
0/32
3/32
7/32
6/32
3/32
7/32
Presumed
Biopsy
Total
1/32 (3%)
2/32 (6%)
3/32 (9%)
lower16 and their reversal with the usual course of SoluMedrol was as easy. No undue renal toxicity could be detected, and the incidence of the most common extrarenal toxic manifestations of CyA5,6,17 (ie, hypertension, hirsutism, gingival hypertrophy, and neurological problems) was in no way more frequent or more severe. In conclusion, the new CyA formulation offers a valid alternative to SIM. Using CON de novo in renal transplant recipients provides adequate immunosuppression, with no increase in untoward side effects. These conclusions are, however, always subject to the following unsolved shortcomings: 1. lack of adequate assessment of functioning renal mass; and 2. lack of a sensitive assessment of CyA dosage both regarding immunosuppression and toxicity. REFERENCES 1. Barbari A, Stephan A, Kamel G, et al: Transplant Proc (in press) 2. Masri MA, Barbari A, Stephan A, et al: Transplant Proc 28:1318, 1996 3. Stephan AG, Barbari A, Masri MA, et al: Transplant Proc 28:1348, 1996 4. Thiru S, Maher ER, Hamilton DV, et al: Transplant Proc 15:2846, 1983 5. Wysocki GP, Gretzinger HA, Lacipacis A, et al: Oral Surg 55:274, 1983 6. Kahan BD, Flechner SM, Lorber MJ, et al: World J Surg 10:348, 1986 7. Bach FH, Auchincloss HJ: Transplantation Immunology. New York: Wiley–Liss; 1995, pp 65–76, 95–102 8. Harjula A, Hockerstedt K: Atlas of Clinical Transplantation. Recall Medical Publishers; 1995, pp 25–56 9. Klima J, Mah I, et al: Archives of Clinical Department, Galena, 1989 10. Klima J, Mah I, et al: Proceedings of the First Symposium on Consupren (cyclosporin) 9, April 1991 11. Puretic Z: Institute for Clinical Pharmacology, Dept. of Internal Medicine, University Hospital Center, Zagreb 12. Faulds D, Karen L, Benfield GP: Drug 45(6):953, 1993 13. Akagi A, Reynolds A, Hjelm M: J International Med Res 19:1, 1991 14. Slomowitz LA, Wilkinson A, Hawkins R, et al: Am J Kidney Dis 15:530, 1990 15. Walser M, Drew HH, La France ND: Kidney Int 34:412, 1988 16. Taesh S, Niese D: Transpl Int 7(suppl 1):263, 1994 17. Marumo T, Nakaki T, Hishikawa K, et al: Hypertension (pt 2):764, 1995 18. Goerel J: Clin Pharmacokinet 23:380, 1992