- Email: [email protected]
A survey to determine the blood concentration of cyclosporine 2 hours postdose in stable renal transplant patients
A Survey to Determine the Blood Concentration of Cyclosporine 2 Hours Postdose in Stable Renal Transplant Patients A. Jorga, D.W. Holt, M. Yaqoob, C. Whittaker, and A. Johnston ABSTRACT The current method for monitoring cyclosporine measures predose concentrations (C0). A better method has been developed, namely, measurement of the blood cyclosporine concentration at 2 hours postdose (C2). The aim of this survey was to determine the variability of C0 and C2 concentrations among stable renal transplant patients. One hundred two stable renal transplant patients who were at least 6 months posttransplant were recruited from the renal transplant outpatient clinic. The cyclosporine dose was between 100 and 500 mg daily; all patients had been monitored using C0 concentrations. Blood samples for cyclosporine concentration measurements were taken at both C0 and C2 at two consecutive clinic visits. The within- and between-patient variabilities were calculated using nested analysis of variance. The mean age was 50 years (21 to 81); the mean weight was 75 kg. The mean cyclosporine dose was 3.18 mg/kg/d (1.2 to 8.8). The average serum creatinine was 174 mol/L (77 to 626) and the average cholesterol was 5 mol/L (3 to 9). The mean (⫾SD) C0 concentration was 150 (47.31) g/L and C2 ⫽ 895 (239) g/L. The C0 concentration varied over 16-fold between patients compared to a sevenfold variation in C2. The between-subject coefficient of variation (CV) was 35% for C0 and 30% for C2 and the within subject CV was 23% for C0 and 20% for C2. The results suggest that cyclosporine concentrations at C0 are slightly more variable than those at C2. Whether this modest reduction in variability results in better patient outcomes is the subject of the next phase of this study.
T
HE INTRODUCTION of cyclosporine transformed kidney transplantation. However, 4% to 8% of grafts still fail every year. The two main reasons are organ rejection or nephrotoxicity caused by immunosuppressant drugs taken to prevent rejection. Therapeutic drug monitoring is therefore essential for cyclosporine management.1 C0 or trough monitoring was considered the most facile practice with the old formulation of cyclosporine (Sandimmun, Novartis Pharma, Switzerland), but with the introduction of the Neoral formulation, it became apparent that there were better ways to optimise cyclosporine dosing.2 Absorption profiling relies on adjusting the drug dose by targeting the blood cyclosporine concentration in the first 4 hours after dosing.3 This is done by measuring either the area under the blood cyclosporine concentration-time curve in the first 4 hours postdose (AUC0 – 4) or, more simply, by measuring the blood cyclosporine concentration at 2 hours postdose (C2).2– 4 The advantage of AUC0 – 4 and C2 over conventional trough cyclosporine measurements
for individualizing drug therapy has been shown for liver,5,6 renal,7 and heart transplant recipients.8 In de novo transplant patients this monitoring method has led to lower rejection rates as well as a reduced incidence and severity of adverse reactions.9 However, the use of C2 for cyclosporine monitoring in long-term, stable transplant recipients has not been tested prospectively. In addition, the feasibility of adopting C2 for the routine monitoring of cyclosporine in an outpatient setting has not been studied. This study was designed to investigate whether the advantages of C2 monitoring in the immediate transplant period are borne out in stable transplant patients. From Barts and the London, Clinical Pharmacology, William Harvey Research Institute, London, United Kingdom. Address reprint requests to Dr Anamarija Jorga, Barts and The London, Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK. E-mail: [email protected]
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.10.077
Transplantation Proceedings, 36, 3239 –3241 (2004)
3239
3240
JORGA, HOLT, YAQOOB ET AL Table 1. Demographic Data Characteristics in Stable Renal Patients
Demographic characteristics
Minimum
First quartile
Median
Third quartile
Maximum
Time after transplant (years) Serum creatinine (mol/L) Cyclosporine dose (mg/d) Cyclosporine dose (mg/kg/d) C0 (g/L) C2 (g/L) C0 (g/L/mg/kg) C2 (g/L/mg/kg)
0.4 77 100 1.2 24.5 308 5.34 102.6
2.0 120.9 200 2.5 116.7 750.5 37.3 238.05
6.0 149 225 2.9 148.1 870.1 47.9 278.6
10.1 189.3 275 3.6 179.4 1069.4 61.2 338.8
17.3 626 500 8.7 303.5 1502 121.2 720.6
MATERIALS AND METHODS This study to establish the feasibility of C2 monitoring in an outpatient setting was conducted between January 2003 and January 2004. We included all renal transplant recipients who were at least 6 months posttransplant and who agreed to participate in the study, which was approved by the local Ethics Committee. Cyclosporine was administered using concentration-controlled doses based on whole-blood predose measurements. The target range for cyclosporine trough concentrations, measured with a specific monoclonal based immunoassay, was 100 to 150 ng/mL. C2 concentrations were not used to adjust the drug doses and were blinded to the clinicians. The data analysis included paired C2 and C0 concentrations determined on both clinical visits. The mean value for both C0 and C2 was used for analysis for each individual. For C2 concentrations a sampling time of 2 hours ⫾ 15 minutes was tolerated and a stopwatch was used to record C2 times. For these measurements patients were not fasted. Consecutive clinical visit data were recorded for serum creatinine, blood pressure, and concomitant medications. Nested analysis of variance, as described in ISO 5725, was used to analyze the variability of C0 and C2 blood concentrations.10
RESULTS
The majority of patients in this study were Caucasian, originating from the UK. Twenty-one percent of our patient population was from the Indian subcontinent, namely, India, Bangladesh, and Pakistan. The mean age of the patients was 49 years for women and 51 years for men; including 81 recipients of a cadaveric and 17, a living related transplant (for four patients transplanted overseas this information was not available). The median time since transplant was 5.8 years. The median creatinine concentration was 149 mol/L. The median C0 and C2 concentrations were both higher than expected: 148 g/L for C0 and 870 g/L for C2. The median cyclosporine dose was 225 mg/d (2.9 mg/kg/d); the median weight adjusted C0 level was 47.9 g/L/mg/kg; and the median weight adjusted C2 concentration was 278.6 g/L/mg/kg (see Table 1). Nominally our target range was 100 to 150 g/L for C0; for C2 a range of 650 to 1000 g/L was considered optimum.4 Only 43 patients (42%) were within the target for C0, the current method of monitoring cyclosporine in the clinic: 49 patients were above and 10 patients below our current guidelines. For C2, 58 patients were considered optimally dosed; 10 were below and 34 above the putative optimum (see Fig 1). The coefficient of variation (CV%)
between patients for C0 was 28% compared with 23% for C2. At the same time, the within-patient variability for C2 was less than for C0 (19% vs 26%). DISCUSSION
It is the goal of the physician to optimize immunosuppressive therapy to avoid rejection on the one hand and to limit side effects on the other. Today, due to the effective antirejection therapy, the greater long-term peril for patients is calcineurin inhibitor–related adverse effects rather than acute rejection.1 The unexpected finding in our study was that 50% of the stable patient population was above our current target concentration guidelines for C0. Although all the patients underwent predose monitoring, the majority (60%) were within the predefined C2 target. Albeit, there are limited data in the literature on C2 monitoring in stable renal patients, a recent survey conducted in Norway11 in 1032 renal patients showed that patients with C2 concentrations between 700 and 800 g/L showed significantly lower creatinine concentrations than those with C2 concentrations above 950 g/L. Several studies show that C0 does not correlate with the area under the curve (AUC), which is the best indicator of exposure to cyclosporine, or to clinical parameters.12,13 This warrants further investigation to determine whether high C2 concentrations correlate with cyclosporine nephrotoxicity in stable patients and whether C2 measurements would bring additional benefits to our patients. In conclusion, it is reasonable to propose that patients with blood cyclosporine concentrations above the recom-
Fig 1.
C0 and C2 levels in stable renal transplant patients.
CYCLOSPORINE BLOOD CONCENTRATION
mended upper limit of 150 g/L have their dose adjusted to avoid unnecessary drug overexposure. To establish whether C2 monitoring has any clinical benefits in the outpatient setting a prospective study between a group monitored using C2 and another using C0 needs to be conducted.14 REFERENCES 1. Jorga A, Holt DW, Johnston A: Therapeutic drug monitoring of cyclosporine. Transplant Proc 36(Suppl):396S, 2004 2. Belitsky P, Levy GA, Johnston A: Neoral absorption profiling: an evolution in effectiveness. Transplant Proc 32(Suppl):45S, 2000 3. Johnston A, David OJ, Cooney GF: Pharmacokinetic validation of neoral absorption profiling. Transplant Proc 32(Suppl):53S, 2000 4. Cole E, Midtvedt K, Johnston A, et al: Recommendations for the implementation of Neoral C(2) monitoring in clinical practice. Transplantation 73(Suppl):S19, 2002 5. Levy G: C2 monitoring in liver transplantantation with Neoral immunosuppresion: effect of achieving C2 target early on efficacy and safety. Am J Transplant 1(Suppl 1):419, 2001 6. Levy G, Burra P, Cavallari A, et al: Improved clinical outcomes for liver transplant recipients using cyclosporine moni-
3241 toring based on 2-hr post-dose levels (C2). Transplantation 73:953, 2002 7. Cole E, Maham N, Cardella C, et al: Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients. Transplantation 75:2086, 2003 8. Cooney GF, Johnston A: Neoral C-2 monitoring in cardiac transplant patients. Transplant Proc 33:1572, 2001 9. Thervet E, Pfeffer P, Scolari MP, et al: Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 76:903, 2003 10. ISO5725: 1994 accuracy (trueness and precision) of measurement methods and results. London: BSI Group; 1994 11. Midtvedt K, Fauchald P, Bergan S, et al: C2 monitoring in maintenance renal transplant recipients: is it worthwhile? Transplantation 76:1236, 2003 12. Grevel J, Welsh MS, Kahan BD: Cyclosporine monitoring in renal transplantation: area under the curve monitoring is superior to trough-level monitoring. Ther Drug Monit 11:246, 1989 13. Keown PA: New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens 11:619, 2002 14. Jorga A, Johnston A, Holt DW: Patient management by cyclosporine C2 monitoring. Transplantation 77:323, 2004
T
HE INTRODUCTION of cyclosporine transformed kidney transplantation. However, 4% to 8% of grafts still fail every year. The two main reasons are organ rejection or nephrotoxicity caused by immunosuppressant drugs taken to prevent rejection. Therapeutic drug monitoring is therefore essential for cyclosporine management.1 C0 or trough monitoring was considered the most facile practice with the old formulation of cyclosporine (Sandimmun, Novartis Pharma, Switzerland), but with the introduction of the Neoral formulation, it became apparent that there were better ways to optimise cyclosporine dosing.2 Absorption profiling relies on adjusting the drug dose by targeting the blood cyclosporine concentration in the first 4 hours after dosing.3 This is done by measuring either the area under the blood cyclosporine concentration-time curve in the first 4 hours postdose (AUC0 – 4) or, more simply, by measuring the blood cyclosporine concentration at 2 hours postdose (C2).2– 4 The advantage of AUC0 – 4 and C2 over conventional trough cyclosporine measurements
for individualizing drug therapy has been shown for liver,5,6 renal,7 and heart transplant recipients.8 In de novo transplant patients this monitoring method has led to lower rejection rates as well as a reduced incidence and severity of adverse reactions.9 However, the use of C2 for cyclosporine monitoring in long-term, stable transplant recipients has not been tested prospectively. In addition, the feasibility of adopting C2 for the routine monitoring of cyclosporine in an outpatient setting has not been studied. This study was designed to investigate whether the advantages of C2 monitoring in the immediate transplant period are borne out in stable transplant patients. From Barts and the London, Clinical Pharmacology, William Harvey Research Institute, London, United Kingdom. Address reprint requests to Dr Anamarija Jorga, Barts and The London, Clinical Pharmacology, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK. E-mail: [email protected]
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.10.077
Transplantation Proceedings, 36, 3239 –3241 (2004)
3239
3240
JORGA, HOLT, YAQOOB ET AL Table 1. Demographic Data Characteristics in Stable Renal Patients
Demographic characteristics
Minimum
First quartile
Median
Third quartile
Maximum
Time after transplant (years) Serum creatinine (mol/L) Cyclosporine dose (mg/d) Cyclosporine dose (mg/kg/d) C0 (g/L) C2 (g/L) C0 (g/L/mg/kg) C2 (g/L/mg/kg)
0.4 77 100 1.2 24.5 308 5.34 102.6
2.0 120.9 200 2.5 116.7 750.5 37.3 238.05
6.0 149 225 2.9 148.1 870.1 47.9 278.6
10.1 189.3 275 3.6 179.4 1069.4 61.2 338.8
17.3 626 500 8.7 303.5 1502 121.2 720.6
MATERIALS AND METHODS This study to establish the feasibility of C2 monitoring in an outpatient setting was conducted between January 2003 and January 2004. We included all renal transplant recipients who were at least 6 months posttransplant and who agreed to participate in the study, which was approved by the local Ethics Committee. Cyclosporine was administered using concentration-controlled doses based on whole-blood predose measurements. The target range for cyclosporine trough concentrations, measured with a specific monoclonal based immunoassay, was 100 to 150 ng/mL. C2 concentrations were not used to adjust the drug doses and were blinded to the clinicians. The data analysis included paired C2 and C0 concentrations determined on both clinical visits. The mean value for both C0 and C2 was used for analysis for each individual. For C2 concentrations a sampling time of 2 hours ⫾ 15 minutes was tolerated and a stopwatch was used to record C2 times. For these measurements patients were not fasted. Consecutive clinical visit data were recorded for serum creatinine, blood pressure, and concomitant medications. Nested analysis of variance, as described in ISO 5725, was used to analyze the variability of C0 and C2 blood concentrations.10
RESULTS
The majority of patients in this study were Caucasian, originating from the UK. Twenty-one percent of our patient population was from the Indian subcontinent, namely, India, Bangladesh, and Pakistan. The mean age of the patients was 49 years for women and 51 years for men; including 81 recipients of a cadaveric and 17, a living related transplant (for four patients transplanted overseas this information was not available). The median time since transplant was 5.8 years. The median creatinine concentration was 149 mol/L. The median C0 and C2 concentrations were both higher than expected: 148 g/L for C0 and 870 g/L for C2. The median cyclosporine dose was 225 mg/d (2.9 mg/kg/d); the median weight adjusted C0 level was 47.9 g/L/mg/kg; and the median weight adjusted C2 concentration was 278.6 g/L/mg/kg (see Table 1). Nominally our target range was 100 to 150 g/L for C0; for C2 a range of 650 to 1000 g/L was considered optimum.4 Only 43 patients (42%) were within the target for C0, the current method of monitoring cyclosporine in the clinic: 49 patients were above and 10 patients below our current guidelines. For C2, 58 patients were considered optimally dosed; 10 were below and 34 above the putative optimum (see Fig 1). The coefficient of variation (CV%)
between patients for C0 was 28% compared with 23% for C2. At the same time, the within-patient variability for C2 was less than for C0 (19% vs 26%). DISCUSSION
It is the goal of the physician to optimize immunosuppressive therapy to avoid rejection on the one hand and to limit side effects on the other. Today, due to the effective antirejection therapy, the greater long-term peril for patients is calcineurin inhibitor–related adverse effects rather than acute rejection.1 The unexpected finding in our study was that 50% of the stable patient population was above our current target concentration guidelines for C0. Although all the patients underwent predose monitoring, the majority (60%) were within the predefined C2 target. Albeit, there are limited data in the literature on C2 monitoring in stable renal patients, a recent survey conducted in Norway11 in 1032 renal patients showed that patients with C2 concentrations between 700 and 800 g/L showed significantly lower creatinine concentrations than those with C2 concentrations above 950 g/L. Several studies show that C0 does not correlate with the area under the curve (AUC), which is the best indicator of exposure to cyclosporine, or to clinical parameters.12,13 This warrants further investigation to determine whether high C2 concentrations correlate with cyclosporine nephrotoxicity in stable patients and whether C2 measurements would bring additional benefits to our patients. In conclusion, it is reasonable to propose that patients with blood cyclosporine concentrations above the recom-
Fig 1.
C0 and C2 levels in stable renal transplant patients.
CYCLOSPORINE BLOOD CONCENTRATION
mended upper limit of 150 g/L have their dose adjusted to avoid unnecessary drug overexposure. To establish whether C2 monitoring has any clinical benefits in the outpatient setting a prospective study between a group monitored using C2 and another using C0 needs to be conducted.14 REFERENCES 1. Jorga A, Holt DW, Johnston A: Therapeutic drug monitoring of cyclosporine. Transplant Proc 36(Suppl):396S, 2004 2. Belitsky P, Levy GA, Johnston A: Neoral absorption profiling: an evolution in effectiveness. Transplant Proc 32(Suppl):45S, 2000 3. Johnston A, David OJ, Cooney GF: Pharmacokinetic validation of neoral absorption profiling. Transplant Proc 32(Suppl):53S, 2000 4. Cole E, Midtvedt K, Johnston A, et al: Recommendations for the implementation of Neoral C(2) monitoring in clinical practice. Transplantation 73(Suppl):S19, 2002 5. Levy G: C2 monitoring in liver transplantantation with Neoral immunosuppresion: effect of achieving C2 target early on efficacy and safety. Am J Transplant 1(Suppl 1):419, 2001 6. Levy G, Burra P, Cavallari A, et al: Improved clinical outcomes for liver transplant recipients using cyclosporine moni-
3241 toring based on 2-hr post-dose levels (C2). Transplantation 73:953, 2002 7. Cole E, Maham N, Cardella C, et al: Clinical benefits of neoral C2 monitoring in the long-term management of renal transplant recipients. Transplantation 75:2086, 2003 8. Cooney GF, Johnston A: Neoral C-2 monitoring in cardiac transplant patients. Transplant Proc 33:1572, 2001 9. Thervet E, Pfeffer P, Scolari MP, et al: Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion. Transplantation 76:903, 2003 10. ISO5725: 1994 accuracy (trueness and precision) of measurement methods and results. London: BSI Group; 1994 11. Midtvedt K, Fauchald P, Bergan S, et al: C2 monitoring in maintenance renal transplant recipients: is it worthwhile? Transplantation 76:1236, 2003 12. Grevel J, Welsh MS, Kahan BD: Cyclosporine monitoring in renal transplantation: area under the curve monitoring is superior to trough-level monitoring. Ther Drug Monit 11:246, 1989 13. Keown PA: New concepts in cyclosporine monitoring. Curr Opin Nephrol Hypertens 11:619, 2002 14. Jorga A, Johnston A, Holt DW: Patient management by cyclosporine C2 monitoring. Transplantation 77:323, 2004