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Optimization of cyclosporine therapy in liver transplantation
Optimization of Cyclosporine Therapy in Liver Transplantation S.G. Pollard and J.P.A. Lodge
A
THOUGH the introduction of cyclosporine (CyA) led to an unquestioned improvement in survival following liver transplantation, debate still exists as to how best to use the drug. Many of the difficulties experienced in using CyA reflect its variable bioavailability. Reduced bile flow and bile diversion through a T-tube, together with a degree of ileus following liver transplantation, led to very inconsistent absorption of Sandimmune, the original formulation of cyclosporine,1 and necessitated the use of intravenous CyA in the early posttransplant period despite problems with toxicity of the IV preparation.2 Traditionally, CyA is given every 12 hours and reaches a peak concentration (Cmax) during the first few hours (Tmax) after ingestion and then the concentration decays to a minimum level (Cmin) when the next dose is given. Therapy is started using a mg/kg/day calculation, and the dose is adjusted to achieve a Cmin or trough level within a defined target range. The need for a target range reflects the problems of drug toxicity, particularly to the kidney and nervous system. Toxicity is generally dose related and usually reflects overexposure. Data from renal transplant recipients3 suggests that with CyA therapy, freedom from rejection correlates with total drug exposure, which equates to the area under the concentration/time curve (AUC). Experimental work suggests that the peak CyA concentration achieved determines the degree of calcineurin inhibition, which in turn determines the immunosuppressive activity.4 Despite being the traditional parameter to measure and adjust the dosage by, the trough level (Cmin) is a poor marker of both AUC and Cmax, and although the correlation is better with Neoral than with Sandimmune, it is not a good surrogate marker for either.5 The original oil-based preparation, Sandimmune, has now been largely replaced with the newer formulation, Neoral, in which CyA is presented in combination with hydrophilic and lipophilic solvents and co-solvents and surfactant.6 The emulsifying and solubilizing action of the vehicle carrier has led to a reduction of both inter- and intrapatient variability and has reduced the effect of bile flow and fed/fasted state on drug absorption.7 Having confirmed improved and less variable bioavailability for Neoral in liver transplantation,7 recent trials have been aimed at (1) using Neoral in patients who are unable to achieve adequate CyA levels on Sandimmune, (2) transfer-
ring stable liver transplant patients from Sandimmune to Neoral, (3) comparing the safety and efficacy of Neoral with Sandimmune and questioning the need for IV CyA in Neoral-treated patients, and (4) reconsidering the way in which CyA therapy is monitored.
USE OF NEORAL IN PATIENTS UNABLE TO ABSORB SANDIMMUNE
Early studies8 evaluated Neoral in patients who were unable to achieve therapeutic CyA blood levels on oral Sandimmune, with Neoral available on a compassionate basis prior to licensing. Subjects included patients with cholestasis, biliary diversion via a t-tube, and malabsorption from cystic fibrosis, and the conversion was made if .1 g of Sandimmune was being administered per day. It was a consistent finding that Neoral had considerably better bioavailability in these groups of patients, and therapeutic levels were achieved without recourse to excessive dosages or the IV preparation. Improved bioavailability was also demonstrated in children who were poor absorbers of the Sandimmune formulation.9
TRANSFER OF STABLE LIVER TRANSPLANT PATIENTS FROM SANDIMMUNE TO NEORAL
In a pilot study from Leeds, UK, it was demonstrated that outpatient conversion of stable liver graft patients .3 months’ posttransplant from Sandimmune to Neoral was logistically straightforward and well tolerated, with no immunological problems and no additional toxicity as measured by parameters such as serum creatinine, need for anti-hypertensive treatment, or the incidence of infections. Improved bioavailability was demonstrated in this study, and a 10% to 15% reduction of dosage was observed to maintain comparable levels.10
From Department of Organ Transplantation, St. James’s University Hospital, Leeds, LS9 7TF UK. Address reprint requests to S.G. Pollard, Department of Organ Transplantation, St. James’s University Hospital, Beckett St, Leeds, LS9 7TF UK.
0041-1345/98/$19.00 PII S0041-1345(98)00443-6
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1816
Transplantation Proceedings, 30, 1816–1818 (1998)
CYA THERAPY IN LIVER TRANSPLANT
COMPARISON OF THE SAFETY AND EFFICACY OF NEORAL WITH SANDIMMUNE, AND THE NEED OF IV CYCLOSPORINE
A single-center study from the Mayo Clinic showed no difference in acute rejection rates when IV CyA was followed by Sandimmune (53% rejection incidence) or Neoral (56%).11 This was consistent with a single-center study from Birmingham, UK, which showed rejection rates of 48% with Sandimmune and 46% with Neoral when these drugs were introduced following IV CyA induction. In this study, however, Neoral p.o. was administered from the day of transplantation to a third group without IV drug, and the rejection incidence in this group was only 22% (personal communication, A.D. Meyer, 1998). This was followed by a study from the same unit12 in which 99 patients receiving Neoral p.o. from the outset were compared with 67 patients receiving IV CyA followed by oral Sandimmune. The number of patients suffering rejection was cut in half (25% vs 50%) in the Neoral group at 2 weeks, and the total number of rejection episodes at 3 months similarly less (30% vs 66%). Although the peak creatinine was higher in the former group, the need for dialysis was no greater. In a recent Canadian study,13 oral Neoral was compared with IV CyA followed by Sandimmune, and the rejection rate of 25% in the Neoral group compared favorably with 65% in the IV plus Sandimmune group. In a Danish study, Rasmussen et al14 compared orally administered Neoral with anti-thymocyte globulin (ATG) induction followed by Sandimmune. The incidence of acute rejection was 24% compared with 52% in the ATG group. The method of administration of Neoral (liquid or capsules) had no effect on outcome, and there was no difference in toxicity between the two groups. Although therapeutic levels are achieved rapidly after starting oral therapy with Neoral, allowing earlier cessation of IV therapy or even avoiding its use altogether, the bioavailability of the drug continues to improve during the early postoperative period, and thus frequent monitoring is recommended. Rasmussen et al14 found that the absorption of Neoral improved during the first 2 weeks, and a multicenter UK study (Neo 004) showed that absorption increased with increased Cmax, and shorter Tmax (but no difference in Cmin) over the first 5 days. In that study, therapeutic levels (150 to 250 ng/mL) were achieved by 48 hours in 93% of patients.15 A major advantage of Neoral is that it has largely removed the need for IV CyA in the early postoperative period. The reason for the unfavourable effect of IV CyA on the incidence of acute rejection is unclear, but similar findings have been observed in renal transplantation and may be related to the method of administration. Because of the toxicity of its carrier, IV CyA is generally given as an infusion over 4 or 12 hours as rapid injection can induce seizures. By this method of administration, the same high peaks seen with orally administered Neoral will not be achieved, and this may lead to suboptimal inhibition of
1817
calcineurin, which has been shown to require high levels of drug in vitro,4 and this may explain the increased incidence of rejection. RECONSIDERING METHODS OF MONITORING CYCLOSPORINE THERAPY
The Canadian study, NOF 08 has performed pharmacokinetic profiles on patients receiving either Neoral or Sandimmune following liver transplantation. The most accurate marker of the maximum concentration was found to be the 2-hour post-dose level, and this proved to be a good surrogate marker of the AUC. There was poor correlation between Cmax and Cmin, and between Cmin and AUC in that study.5 The incidence of acute rejection did not bear any relationship to the Cmin level, but was inversely related to the Cmax and AUC. Two-hour levels of .800 ng/mL appeared to protect from acute rejection. This was not influenced by the formulation given, but patients receiving Neoral were more likely to attain peak levels in this range than were patients taking Sandimmune. It remains unclear whether efficacy is related to total exposure (AUC) or the peak, because there is a reasonable correlation between the two with Neoral. Based on the results from the NOF 08 study, Neo Int 06 is now underway in Europe and North America to randomize patients to monitoring by 2-hour levels (target range 850 to 1400 ng/mL) or 12-hour levels (target range 250 to 400 ng/mL) and observing outcomes. The aim of the study is to determine whether efficacy can be improved by dosing by a more relevant marker of exposure. In addition, toxicity might be reduced by avoiding the very high peaks that usually occur unobserved in some patients monitored by traditional methods. OTHER TRIALS IN PROGRESS
A UK multicenter head-to-head comparison of Neoral with tacrolimus is now underway, although the preliminary data (3 months) from an equivalent Canadian study of 140 patients shows no significant difference between the drugs in terms of safety, efficacy, or tolerability (personal communication, G. Levy, 1998). Studies are also in progress looking at combination therapy with the antiproliferative agent mycophenolate mofetil (MMF), as the earlier experience with MMF had been in combination with Sandimmune rather than with Neoral. Possible synergism is also being explored with newer agents that are awaiting licencing. These include the monoclonal antibody CHI 621 and rapamycin and its analog RAD655. Other potential areas for development are the introduction of a desktop monitor that can give an immediate CyA level on a single drop of blood and the aggressive treatment of co-morbidity attributed to CyA therapy, particularly hypertension and hyperlipidemia, on the basis that long-
1818
term death from cardiac causes with a functioning graft remains a significant cause of graft loss. Finally, it is interesting to consider that even after so many years of using cyclosporine, one can still see areas for change and improvement in the ways we use the drug. REFERENCES 1. Beverdige T, Gratwohl A, Michot F, et al: Curr Ther Res 30:5, 1981 2. Muller R: Transplantation 58:155, 1994 3. Lindholm A, Kahan BD: Clin Pharmacol Ther 54:208, 1993 4. Batiuk TD, Pazderka F, Enns J, et al: J Clin Invest 96:1254, 1995 5. Grant DR, Kneteman NM, Tchervenkov, et al: Transplantation (in press)
POLLARD AND LODGE 6. Vonderscher J, Meinzer A: Transplant Proc 26:2925, 1994 7. Freeman D, Grant D, Levy GA, et al: Ther Drug Monit 17:213, 1995 8. Trull AK, Tan KKC, Uttrdige J, et al: Lancet 341:433, 1993 9. Superina RA, Strong DK, Acal LA, et al: Transplant Proc 26:2979, 1994 10. Pollard SG, Lodge JPA: Transplant Proc 28:2244, 1996 11. Graziadei IW, Weisner RH, Marotta PJ, et al: Transplantation 64:726, 1997 12. Mirza DF, Gunson BK, Soonawalla Z, et al: Lancet 349:701, 1997 13. Hemming AW, Greig PD, Cattral MS: Transplant Proc 29:543, 1997 14. Rasmussen A, Horrtup A, Hansen BA, et al: Transplantation (in press) 15. Tredger M: Ther Drug Monit 17:638, 1995
A
THOUGH the introduction of cyclosporine (CyA) led to an unquestioned improvement in survival following liver transplantation, debate still exists as to how best to use the drug. Many of the difficulties experienced in using CyA reflect its variable bioavailability. Reduced bile flow and bile diversion through a T-tube, together with a degree of ileus following liver transplantation, led to very inconsistent absorption of Sandimmune, the original formulation of cyclosporine,1 and necessitated the use of intravenous CyA in the early posttransplant period despite problems with toxicity of the IV preparation.2 Traditionally, CyA is given every 12 hours and reaches a peak concentration (Cmax) during the first few hours (Tmax) after ingestion and then the concentration decays to a minimum level (Cmin) when the next dose is given. Therapy is started using a mg/kg/day calculation, and the dose is adjusted to achieve a Cmin or trough level within a defined target range. The need for a target range reflects the problems of drug toxicity, particularly to the kidney and nervous system. Toxicity is generally dose related and usually reflects overexposure. Data from renal transplant recipients3 suggests that with CyA therapy, freedom from rejection correlates with total drug exposure, which equates to the area under the concentration/time curve (AUC). Experimental work suggests that the peak CyA concentration achieved determines the degree of calcineurin inhibition, which in turn determines the immunosuppressive activity.4 Despite being the traditional parameter to measure and adjust the dosage by, the trough level (Cmin) is a poor marker of both AUC and Cmax, and although the correlation is better with Neoral than with Sandimmune, it is not a good surrogate marker for either.5 The original oil-based preparation, Sandimmune, has now been largely replaced with the newer formulation, Neoral, in which CyA is presented in combination with hydrophilic and lipophilic solvents and co-solvents and surfactant.6 The emulsifying and solubilizing action of the vehicle carrier has led to a reduction of both inter- and intrapatient variability and has reduced the effect of bile flow and fed/fasted state on drug absorption.7 Having confirmed improved and less variable bioavailability for Neoral in liver transplantation,7 recent trials have been aimed at (1) using Neoral in patients who are unable to achieve adequate CyA levels on Sandimmune, (2) transfer-
ring stable liver transplant patients from Sandimmune to Neoral, (3) comparing the safety and efficacy of Neoral with Sandimmune and questioning the need for IV CyA in Neoral-treated patients, and (4) reconsidering the way in which CyA therapy is monitored.
USE OF NEORAL IN PATIENTS UNABLE TO ABSORB SANDIMMUNE
Early studies8 evaluated Neoral in patients who were unable to achieve therapeutic CyA blood levels on oral Sandimmune, with Neoral available on a compassionate basis prior to licensing. Subjects included patients with cholestasis, biliary diversion via a t-tube, and malabsorption from cystic fibrosis, and the conversion was made if .1 g of Sandimmune was being administered per day. It was a consistent finding that Neoral had considerably better bioavailability in these groups of patients, and therapeutic levels were achieved without recourse to excessive dosages or the IV preparation. Improved bioavailability was also demonstrated in children who were poor absorbers of the Sandimmune formulation.9
TRANSFER OF STABLE LIVER TRANSPLANT PATIENTS FROM SANDIMMUNE TO NEORAL
In a pilot study from Leeds, UK, it was demonstrated that outpatient conversion of stable liver graft patients .3 months’ posttransplant from Sandimmune to Neoral was logistically straightforward and well tolerated, with no immunological problems and no additional toxicity as measured by parameters such as serum creatinine, need for anti-hypertensive treatment, or the incidence of infections. Improved bioavailability was demonstrated in this study, and a 10% to 15% reduction of dosage was observed to maintain comparable levels.10
From Department of Organ Transplantation, St. James’s University Hospital, Leeds, LS9 7TF UK. Address reprint requests to S.G. Pollard, Department of Organ Transplantation, St. James’s University Hospital, Beckett St, Leeds, LS9 7TF UK.
0041-1345/98/$19.00 PII S0041-1345(98)00443-6
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1816
Transplantation Proceedings, 30, 1816–1818 (1998)
CYA THERAPY IN LIVER TRANSPLANT
COMPARISON OF THE SAFETY AND EFFICACY OF NEORAL WITH SANDIMMUNE, AND THE NEED OF IV CYCLOSPORINE
A single-center study from the Mayo Clinic showed no difference in acute rejection rates when IV CyA was followed by Sandimmune (53% rejection incidence) or Neoral (56%).11 This was consistent with a single-center study from Birmingham, UK, which showed rejection rates of 48% with Sandimmune and 46% with Neoral when these drugs were introduced following IV CyA induction. In this study, however, Neoral p.o. was administered from the day of transplantation to a third group without IV drug, and the rejection incidence in this group was only 22% (personal communication, A.D. Meyer, 1998). This was followed by a study from the same unit12 in which 99 patients receiving Neoral p.o. from the outset were compared with 67 patients receiving IV CyA followed by oral Sandimmune. The number of patients suffering rejection was cut in half (25% vs 50%) in the Neoral group at 2 weeks, and the total number of rejection episodes at 3 months similarly less (30% vs 66%). Although the peak creatinine was higher in the former group, the need for dialysis was no greater. In a recent Canadian study,13 oral Neoral was compared with IV CyA followed by Sandimmune, and the rejection rate of 25% in the Neoral group compared favorably with 65% in the IV plus Sandimmune group. In a Danish study, Rasmussen et al14 compared orally administered Neoral with anti-thymocyte globulin (ATG) induction followed by Sandimmune. The incidence of acute rejection was 24% compared with 52% in the ATG group. The method of administration of Neoral (liquid or capsules) had no effect on outcome, and there was no difference in toxicity between the two groups. Although therapeutic levels are achieved rapidly after starting oral therapy with Neoral, allowing earlier cessation of IV therapy or even avoiding its use altogether, the bioavailability of the drug continues to improve during the early postoperative period, and thus frequent monitoring is recommended. Rasmussen et al14 found that the absorption of Neoral improved during the first 2 weeks, and a multicenter UK study (Neo 004) showed that absorption increased with increased Cmax, and shorter Tmax (but no difference in Cmin) over the first 5 days. In that study, therapeutic levels (150 to 250 ng/mL) were achieved by 48 hours in 93% of patients.15 A major advantage of Neoral is that it has largely removed the need for IV CyA in the early postoperative period. The reason for the unfavourable effect of IV CyA on the incidence of acute rejection is unclear, but similar findings have been observed in renal transplantation and may be related to the method of administration. Because of the toxicity of its carrier, IV CyA is generally given as an infusion over 4 or 12 hours as rapid injection can induce seizures. By this method of administration, the same high peaks seen with orally administered Neoral will not be achieved, and this may lead to suboptimal inhibition of
1817
calcineurin, which has been shown to require high levels of drug in vitro,4 and this may explain the increased incidence of rejection. RECONSIDERING METHODS OF MONITORING CYCLOSPORINE THERAPY
The Canadian study, NOF 08 has performed pharmacokinetic profiles on patients receiving either Neoral or Sandimmune following liver transplantation. The most accurate marker of the maximum concentration was found to be the 2-hour post-dose level, and this proved to be a good surrogate marker of the AUC. There was poor correlation between Cmax and Cmin, and between Cmin and AUC in that study.5 The incidence of acute rejection did not bear any relationship to the Cmin level, but was inversely related to the Cmax and AUC. Two-hour levels of .800 ng/mL appeared to protect from acute rejection. This was not influenced by the formulation given, but patients receiving Neoral were more likely to attain peak levels in this range than were patients taking Sandimmune. It remains unclear whether efficacy is related to total exposure (AUC) or the peak, because there is a reasonable correlation between the two with Neoral. Based on the results from the NOF 08 study, Neo Int 06 is now underway in Europe and North America to randomize patients to monitoring by 2-hour levels (target range 850 to 1400 ng/mL) or 12-hour levels (target range 250 to 400 ng/mL) and observing outcomes. The aim of the study is to determine whether efficacy can be improved by dosing by a more relevant marker of exposure. In addition, toxicity might be reduced by avoiding the very high peaks that usually occur unobserved in some patients monitored by traditional methods. OTHER TRIALS IN PROGRESS
A UK multicenter head-to-head comparison of Neoral with tacrolimus is now underway, although the preliminary data (3 months) from an equivalent Canadian study of 140 patients shows no significant difference between the drugs in terms of safety, efficacy, or tolerability (personal communication, G. Levy, 1998). Studies are also in progress looking at combination therapy with the antiproliferative agent mycophenolate mofetil (MMF), as the earlier experience with MMF had been in combination with Sandimmune rather than with Neoral. Possible synergism is also being explored with newer agents that are awaiting licencing. These include the monoclonal antibody CHI 621 and rapamycin and its analog RAD655. Other potential areas for development are the introduction of a desktop monitor that can give an immediate CyA level on a single drop of blood and the aggressive treatment of co-morbidity attributed to CyA therapy, particularly hypertension and hyperlipidemia, on the basis that long-
1818
term death from cardiac causes with a functioning graft remains a significant cause of graft loss. Finally, it is interesting to consider that even after so many years of using cyclosporine, one can still see areas for change and improvement in the ways we use the drug. REFERENCES 1. Beverdige T, Gratwohl A, Michot F, et al: Curr Ther Res 30:5, 1981 2. Muller R: Transplantation 58:155, 1994 3. Lindholm A, Kahan BD: Clin Pharmacol Ther 54:208, 1993 4. Batiuk TD, Pazderka F, Enns J, et al: J Clin Invest 96:1254, 1995 5. Grant DR, Kneteman NM, Tchervenkov, et al: Transplantation (in press)
POLLARD AND LODGE 6. Vonderscher J, Meinzer A: Transplant Proc 26:2925, 1994 7. Freeman D, Grant D, Levy GA, et al: Ther Drug Monit 17:213, 1995 8. Trull AK, Tan KKC, Uttrdige J, et al: Lancet 341:433, 1993 9. Superina RA, Strong DK, Acal LA, et al: Transplant Proc 26:2979, 1994 10. Pollard SG, Lodge JPA: Transplant Proc 28:2244, 1996 11. Graziadei IW, Weisner RH, Marotta PJ, et al: Transplantation 64:726, 1997 12. Mirza DF, Gunson BK, Soonawalla Z, et al: Lancet 349:701, 1997 13. Hemming AW, Greig PD, Cattral MS: Transplant Proc 29:543, 1997 14. Rasmussen A, Horrtup A, Hansen BA, et al: Transplantation (in press) 15. Tredger M: Ther Drug Monit 17:638, 1995