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Clinical Impact of Neoral in Heart Transplantation
Clinical Impact of Neoral in Heart Transplantation T. Aziz, A. El-Gamel, B. Keevil, R. Martyszczuk, C. Campbell, A. Rahman, A. Deiraniya, and N. Yonan
T
HE INTRODUCTION of cyclosporine as an immunosuppressive agent in the clinical heart transplantation in 1979 has been associated with an improvement in short-term and long-term survival rates, largely because of a decrease in the mortality from rejection and infection.1 However, the large intra- and interindividual variability of cyclosporine absorption with the Sandimmune formulation has necessitated frequent monitoring of blood concentrations to reliably prevent graft rejection and minimise adverse effect.2 Neoral is a new oral formulation of cyclosporine. It is a microemulsion preconcentrate comprising the active drug (cyclosporine) together with a surfactant, a lipophilic solvent, a hydrophilic solvent, and a hydrophilic cosolvent.3 The aim of this study was to assess the safety, tolerability, and side effects of Neoral in heart transplant recipients.
PATIENTS AND METHODS The Patients One hundred thirty-eight heart transplant recipients with stable allograft function receiving triple therapy with CyA, azathioprine, and prednisolone were enrolled in this study. Mean patient age was 44 6 2.2 years (range 17 to 67). Transplantation was performed 42.3 6 10.5 months (range 6 to 103 months) prior to the beginning of the study. Patients with poor graft function, poor kidney function (creatinine .250 mmol), active infection, lymphoproliferative disorder, or history of malignancy were excluded.
The Study For at least 2 weeks before study entry, all patients received cyclosporine as Sandimmune, with the total daily dose divided into two equal doses administrated every 12 hour. Doses were individualised to provide stable morning whole-blood trough concentration within the target therapeutic range.
Conversion Protocol All patients had full clinical and laboratory assessment, which included trough CyA, serum urea, and serum creatinine. Then patients were converted to Neoral on 1:1 mg basis. Clinical and laboratory assessment were repeated at week 1, week 4, week 8 and, week 12. Neoral dose was adjusted to maintain CyA trough level comparable to CyA at study entry. Tolerability and safety were monitored over the study duration at weekly clinic appointments. At each visit, weight, heart rate, blood pressure, and ECG were recorded. An echocardiogram was performed if clinically indicated, and heart biopsy was performed at the usual routine intervals unless otherwise clinically indicated to be brought forward.
RESULTS Dosing and Level
There was a significant rise in CyA level from 158 6 74 ng/mL to 174 6 67 ng/mL (P 5 .008) despite a dose reduction of 10% at week 4 (P 5 .0001). After 3 months period, at week 12 there was an other further 11% dose reduction (P 5 .0001) to maintain CyA of 171 6 44 ng/mL. Full details of dose and level changes during the study are listed in Table 1. Kidney Function
Initially, we recorded reduction in the average creatinine level (Table 1). However, there was large interindividual variability, as 48% (n 5 67) of the patients had 10% drop in the mean serum creatinine following conversion level from 170 6 43 mmol/L at week 0 to 153 6 45 mmol/L at week 4 (P , .0004), while 27% (n 5 38) had 8% rise in the mean serum creatinine from 184 6 10 mmol/L at week 0 to 199 6 From the Department of Transplantation Surgery, Wythenshawe Hospital, Manchester, UK.
Table 1. Changes in Cyclosporine Pharmacokinetics for 138 Heart Transplant Recipients During the First 3 Months After Starting Neoral
CyA dose mg CyA level ng/mL Urea Creatinine Umol/L
W0
W4
P W0:W4
W12
P W0:W12
292 6 133.33 158 6 74.14 12 6 5.6 171 6 46.48
261 6 48.7 174 6 67.22 11 6 6.1 159 6 44
.0001 .008 NS .001
231 6 105.33 171 6 44.45 12 6 7.8 163 6 43.25
.0001 .04 NS .02
(Statistical comparison done by paired t test).
0041-1345/98/$19.00 PII S0041-1345(98)00188-2
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1152
Transplantation Proceedings, 30, 1152–1153 (1998)
IMPACT OF NEORAL IN HEART TRANSPLANTATION
15 mmol/L (P , .034) at week 4. Twenty-nine of 38 recipients who recorded deterioration in their kidney function with Neoral had serum creatinine level $175 mmol/L prior to conversion. The rest of the recipients (n 5 33 patients) did not show any significant change in their serum creatinine level. At week 12, the kidney function for most of the recipients was stable, and the mean serum creatinine level was 162 6 43 mmol/L. There was no significant difference in urea level at any stage of the study, and there was no change in the pattern or incidence of rejection through the study period. General Side Effects
Twenty-three percent of the recipients in this study developed various side effects that ranged from gastrointestinal disturbance in 17% (anorexia, nausea, vomiting) headache in 14%, hypertension in 8%, tremors in 3%, gout in 3%, or sleep disturbance in 1%. These occurred at an early stage following conversion. However, most of undesirable side effects disappeared with dose reduction at weeks 4 and 12. DISCUSSION
Cyclosporine is a cornerstone of most immunosuppressive protocols used in transplantation of solid organs and bone marrow.4 It has also been used for treatment of several autoimmune diseases.5 The immunosuppressive effectiveness of this drug is well documented and the results of clinical transplantation have improved since its introduction.6 However, a number of side effects of CyA have been reported, including nephro-, neuro-, and hepatotoxicity. Most of the side effects are dose dependent. Therefore careful adjustments of drug dosage have been necessary.7 This has been difficult to manage since the absorption of CyA from Sandimmune is erratic, leading to high intra- and interindividual variability in its pharmacokinetic parameters.8 The microemulsion-based formulation of cyclosporine (Neoral) has been developed to overcome problems associated with poor absorption of Sandimmune. As anticipated, absorption-related trough CyA level difference between the two formulations were evident after 1:1 mg conversion to Neoral. This result was similar to reported pharmacokinetics profile of Neoral metabolism in renal and liver recipients.9 –11 A further dose-sparing effect during a 3-month period following conversion was demonstrated in this study. This suggests that a period longer than 4 weeks is needed to reach a stable dose-trough level equilibrium under clinical conditions. Despite all demonstrated improvement, toxicity, especially renal toxicity, remains a point of potential concern. In
1153
this study, despite of significant rise in Cmin, this study recorded lower or similar mean serum creatinine level in 70% of the recipients, however, 30% of the recipients developed a significant rise in serum creatinine level during the conversion. The higher risk of developing nephrotoxicity was in recipients with serum creatinine .175 mmol/L before conversion. Three months after conversion, the kidney function of most of the recipients was stable. Increased bioavailability following conversion to Neoral with minimal renal toxicity had been previously reported in heart transplant recipients.12 In addition to improved trough cyclosporine level with maintained kidney function in the majority of our recipients, there was no significant change in the incidence of rejection following the conversion to Neoral. Recently we reported that a trough CyA level of more than 200 ng/mL in the first 2 years after heart transplantation is associated with reduced incidence of significant cellular rejection, which confirms the importance of achieving high stable trough CyA level with Neoral therapy.13 We conclude that conversion of the heart transplant recipients from Sandimmune to Neoral is safe and well tolerated. Neoral offers greater exposure to CyA in spite of the overall dose reduction (20 to 21%). Regarding limited financial resources in organs transplantation, especially under pharmacoeconomic aspect, this dose reduction represents a considerable cost-saving factor. REFERENCES 1. McCarthy N: Clin Monit 11:172, 1988 2. Holt D, Mueller E, Kovarick J, et al: Transplant Proc 27:1434, 1995 3. Schroeder T, Harihan S, Fierst M: Transplant Proc 26:2787, 1994 4. Kahan BD: N Engl J Med 321:1725, 1989 5. Feutren G: Transplant Proc 24:55, 1992 6. Margreiter R: Transplant Proc 23:2180, 1991 7. Gruber SA, Chan GLC, Canafax DM, et al: Clin Transplant 5:65, 1991 8. Lindholm A, Henricsson S, Lind M, et al: Euro J Pharmacol 34:461, 1988 9. Gaspari F, Ruggenenti P, Torre I, et al: Kidney Int 44:436, 1993 10. Freeman D, Grant D, Levy G, et al: Ther Drug Monit 17:213, 1995 11. Pirsch J, D’Alessandro A, Knechtle S, et al: Transplant Proc 25(suppl 3):15, 1993 12. Darymple M, Meara M, Renolds L, et al: Transplant Proc 28:2285, 1996 13. El Gamel A, Keevil B, Dip CB, et al: J Heart Lung Transplant 16:268, 1997
T
HE INTRODUCTION of cyclosporine as an immunosuppressive agent in the clinical heart transplantation in 1979 has been associated with an improvement in short-term and long-term survival rates, largely because of a decrease in the mortality from rejection and infection.1 However, the large intra- and interindividual variability of cyclosporine absorption with the Sandimmune formulation has necessitated frequent monitoring of blood concentrations to reliably prevent graft rejection and minimise adverse effect.2 Neoral is a new oral formulation of cyclosporine. It is a microemulsion preconcentrate comprising the active drug (cyclosporine) together with a surfactant, a lipophilic solvent, a hydrophilic solvent, and a hydrophilic cosolvent.3 The aim of this study was to assess the safety, tolerability, and side effects of Neoral in heart transplant recipients.
PATIENTS AND METHODS The Patients One hundred thirty-eight heart transplant recipients with stable allograft function receiving triple therapy with CyA, azathioprine, and prednisolone were enrolled in this study. Mean patient age was 44 6 2.2 years (range 17 to 67). Transplantation was performed 42.3 6 10.5 months (range 6 to 103 months) prior to the beginning of the study. Patients with poor graft function, poor kidney function (creatinine .250 mmol), active infection, lymphoproliferative disorder, or history of malignancy were excluded.
The Study For at least 2 weeks before study entry, all patients received cyclosporine as Sandimmune, with the total daily dose divided into two equal doses administrated every 12 hour. Doses were individualised to provide stable morning whole-blood trough concentration within the target therapeutic range.
Conversion Protocol All patients had full clinical and laboratory assessment, which included trough CyA, serum urea, and serum creatinine. Then patients were converted to Neoral on 1:1 mg basis. Clinical and laboratory assessment were repeated at week 1, week 4, week 8 and, week 12. Neoral dose was adjusted to maintain CyA trough level comparable to CyA at study entry. Tolerability and safety were monitored over the study duration at weekly clinic appointments. At each visit, weight, heart rate, blood pressure, and ECG were recorded. An echocardiogram was performed if clinically indicated, and heart biopsy was performed at the usual routine intervals unless otherwise clinically indicated to be brought forward.
RESULTS Dosing and Level
There was a significant rise in CyA level from 158 6 74 ng/mL to 174 6 67 ng/mL (P 5 .008) despite a dose reduction of 10% at week 4 (P 5 .0001). After 3 months period, at week 12 there was an other further 11% dose reduction (P 5 .0001) to maintain CyA of 171 6 44 ng/mL. Full details of dose and level changes during the study are listed in Table 1. Kidney Function
Initially, we recorded reduction in the average creatinine level (Table 1). However, there was large interindividual variability, as 48% (n 5 67) of the patients had 10% drop in the mean serum creatinine following conversion level from 170 6 43 mmol/L at week 0 to 153 6 45 mmol/L at week 4 (P , .0004), while 27% (n 5 38) had 8% rise in the mean serum creatinine from 184 6 10 mmol/L at week 0 to 199 6 From the Department of Transplantation Surgery, Wythenshawe Hospital, Manchester, UK.
Table 1. Changes in Cyclosporine Pharmacokinetics for 138 Heart Transplant Recipients During the First 3 Months After Starting Neoral
CyA dose mg CyA level ng/mL Urea Creatinine Umol/L
W0
W4
P W0:W4
W12
P W0:W12
292 6 133.33 158 6 74.14 12 6 5.6 171 6 46.48
261 6 48.7 174 6 67.22 11 6 6.1 159 6 44
.0001 .008 NS .001
231 6 105.33 171 6 44.45 12 6 7.8 163 6 43.25
.0001 .04 NS .02
(Statistical comparison done by paired t test).
0041-1345/98/$19.00 PII S0041-1345(98)00188-2
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1152
Transplantation Proceedings, 30, 1152–1153 (1998)
IMPACT OF NEORAL IN HEART TRANSPLANTATION
15 mmol/L (P , .034) at week 4. Twenty-nine of 38 recipients who recorded deterioration in their kidney function with Neoral had serum creatinine level $175 mmol/L prior to conversion. The rest of the recipients (n 5 33 patients) did not show any significant change in their serum creatinine level. At week 12, the kidney function for most of the recipients was stable, and the mean serum creatinine level was 162 6 43 mmol/L. There was no significant difference in urea level at any stage of the study, and there was no change in the pattern or incidence of rejection through the study period. General Side Effects
Twenty-three percent of the recipients in this study developed various side effects that ranged from gastrointestinal disturbance in 17% (anorexia, nausea, vomiting) headache in 14%, hypertension in 8%, tremors in 3%, gout in 3%, or sleep disturbance in 1%. These occurred at an early stage following conversion. However, most of undesirable side effects disappeared with dose reduction at weeks 4 and 12. DISCUSSION
Cyclosporine is a cornerstone of most immunosuppressive protocols used in transplantation of solid organs and bone marrow.4 It has also been used for treatment of several autoimmune diseases.5 The immunosuppressive effectiveness of this drug is well documented and the results of clinical transplantation have improved since its introduction.6 However, a number of side effects of CyA have been reported, including nephro-, neuro-, and hepatotoxicity. Most of the side effects are dose dependent. Therefore careful adjustments of drug dosage have been necessary.7 This has been difficult to manage since the absorption of CyA from Sandimmune is erratic, leading to high intra- and interindividual variability in its pharmacokinetic parameters.8 The microemulsion-based formulation of cyclosporine (Neoral) has been developed to overcome problems associated with poor absorption of Sandimmune. As anticipated, absorption-related trough CyA level difference between the two formulations were evident after 1:1 mg conversion to Neoral. This result was similar to reported pharmacokinetics profile of Neoral metabolism in renal and liver recipients.9 –11 A further dose-sparing effect during a 3-month period following conversion was demonstrated in this study. This suggests that a period longer than 4 weeks is needed to reach a stable dose-trough level equilibrium under clinical conditions. Despite all demonstrated improvement, toxicity, especially renal toxicity, remains a point of potential concern. In
1153
this study, despite of significant rise in Cmin, this study recorded lower or similar mean serum creatinine level in 70% of the recipients, however, 30% of the recipients developed a significant rise in serum creatinine level during the conversion. The higher risk of developing nephrotoxicity was in recipients with serum creatinine .175 mmol/L before conversion. Three months after conversion, the kidney function of most of the recipients was stable. Increased bioavailability following conversion to Neoral with minimal renal toxicity had been previously reported in heart transplant recipients.12 In addition to improved trough cyclosporine level with maintained kidney function in the majority of our recipients, there was no significant change in the incidence of rejection following the conversion to Neoral. Recently we reported that a trough CyA level of more than 200 ng/mL in the first 2 years after heart transplantation is associated with reduced incidence of significant cellular rejection, which confirms the importance of achieving high stable trough CyA level with Neoral therapy.13 We conclude that conversion of the heart transplant recipients from Sandimmune to Neoral is safe and well tolerated. Neoral offers greater exposure to CyA in spite of the overall dose reduction (20 to 21%). Regarding limited financial resources in organs transplantation, especially under pharmacoeconomic aspect, this dose reduction represents a considerable cost-saving factor. REFERENCES 1. McCarthy N: Clin Monit 11:172, 1988 2. Holt D, Mueller E, Kovarick J, et al: Transplant Proc 27:1434, 1995 3. Schroeder T, Harihan S, Fierst M: Transplant Proc 26:2787, 1994 4. Kahan BD: N Engl J Med 321:1725, 1989 5. Feutren G: Transplant Proc 24:55, 1992 6. Margreiter R: Transplant Proc 23:2180, 1991 7. Gruber SA, Chan GLC, Canafax DM, et al: Clin Transplant 5:65, 1991 8. Lindholm A, Henricsson S, Lind M, et al: Euro J Pharmacol 34:461, 1988 9. Gaspari F, Ruggenenti P, Torre I, et al: Kidney Int 44:436, 1993 10. Freeman D, Grant D, Levy G, et al: Ther Drug Monit 17:213, 1995 11. Pirsch J, D’Alessandro A, Knechtle S, et al: Transplant Proc 25(suppl 3):15, 1993 12. Darymple M, Meara M, Renolds L, et al: Transplant Proc 28:2285, 1996 13. El Gamel A, Keevil B, Dip CB, et al: J Heart Lung Transplant 16:268, 1997