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Optimizing neoral therapeutic drug monitoring with cyclosporine trough (C0) and C2 concentrations in stable renal allograft recipients
Optimizing Neoral Therapeutic Drug Monitoring With Cyclosporine Trough (C0) and C2 Concentrations in Stable Renal Allograft Recipients G. Einecke, I. Mai, F. Diekmann, L. Fritsche, T. Boehler, H.-H. Neumayer, and K. Budde
T
HE INTRODUCTION of the immunosuppressive agent cyclosporine (CsA) into clinical practice was a major advance in the prevention and treatment of allograft rejection. However, clinicians soon came to realize the problems associated with dosing of CsA because of the narrow therapeutic window that allows adequate T-cell immunosuppression with minimum risk of side effects. Hypertension and renal dysfunction are common in allograft recipients, and nephrotoxicity secondary to CsA may progress toward end-stage renal failure. The highly variable pharmacokinetics1 have made therapeutic drug monitoring an indispensable tool for management of CsA therapy. By convention, monitoring became targeted to trough level (C0), which is still widely used to guide dose adjustments, although it has been shown that C0 values correlate poorly with total drug exposure and with clinical events in patients after organ transplantation. Although the introduction of the current CsA formulation (Neoral) has led to improved absorption and reduced pharmacokinetic variability, pharmacokinetic studies have shown that the area under the concentration–time curve (AUC) is a more sensitive predictor of acute and chronic rejection, graft survival rate, and nephrotoxicity.2– 4 However, conventional methods of measuring AUC require multiple samples and are therefore inconvenient in clinical practice. In additional studies it was demonstrated that, by using a limited sample strategy (LSS), AUC monitoring can be simplified for use in a routine clinical setting.5 The use of a small number of blood samples collected at specific timepoints provides the basis for estimating the real AUC. Several timepoints have been suggested for AUC prediction; most investigators have used two-point combinations. In particular, sampling times within the first 4 hours have been shown to be accurate, and a gap of 2 hours between the two points has been demonstrated to be compulsory for reliable predictions.5 The sampling of C0 and CsA concentrations at 2 hours postdose (C2) has been shown to be an accurate method of estimating AUC.6,7 As studies in kidney allograft recipients have shown, it seems that C2 alone is also sufficient for prediction of clinical outcome.8 However, there are only limited data for the required C2 levels in stable renal allograft recipients beyond the first 3 months after transplantation. This study
therefore aimed to generate a therapeutic window for C2 values in clinical practice. PATIENTS AND METHODS For method validation full ten-point CsA kinetics were performed in 24 stable patients. In 120 consecutive patients we determined 200 C0 and C2 levels. All patients (age 51.3 ⫾ 12 years, 62.5% male) were on stable Neoral (2.6 ⫾ 0.8 mg/kg per day) medication at 85 ⫾ 59 months after transplantation. In 49 patients, trough levels and C2 values were repeated during the next visit without dose change. All CsA concentrations were measured using a specific monoclonal antibody (EMIT assay, Dade–Behring). Area under the curve (AUC) was calculated using the linear trapezoidal rule and according to a standard formula for two-point AUC (990 ⫹ 10.74 ⴱ C0 ⫹ 2.28 ⴱ C2).
RESULTS
In the 24 full ten-point kinetics there was good correlation between measured ten-point AUC and calculated two-point AUC (r ⫽ .89). C0 showed a correlation with ten-point AUC of r ⫽ .77, which was weaker than the observed correlation of C2 with ten-point AUC (r ⫽ .85). The mean C0 in 120 long-term patients was 104 ⫾ 34 ng/mL, and C2 was 557 ⫾ 185 ng/mL. The mean calculated AUC was 3376 ⫾ 668 ng 䡠 h/mL. Ten percent of the calculated AUC values were ⬍2500 ng 䡠 h/mL, and 16% were ⬎4000 ng 䡠 h/ mL. We found a weak correlation between C0 and C2 (r ⫽ .44). CsA dose did not correlate with AUC, C0, or C2. Repeated determinations (n ⫽ 49) of C0 values showed a correlation of r ⫽ .55; coefficient of variation was 21%. Correlation of repeated C2 values gave better results (r ⫽ .75; coefficient of variation 17%). In the 120 stable renal allograft recipients the mean increase of C0 to C2 was by a factor of 5.6 ⫾ 2.0. Different absorption profiles could be observed in these patients: there was a group of low absorbers (C2/C0 ⬍3.6; 12.5% of From the Departments of Nephrology (G.E., F.D., L.F., T.B., H.-H.N., K.B.) and Clinical Pharmacology (I.M.), Humboldt University, Berlin, Germany. Address reprint requests to Dr G. Einecke, Department of Nephrology, Charite´, Humboldt University, Schumannstr 20121, 10098 Berlin, Germany.
0041-1345/01/$–see front matter PII S0041-1345(01)02322-3
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3102
Transplantation Proceedings, 33, 3102–3103 (2001)
OPTIMIZING NEORAL MONITORING
3103
Table 1. Absorption Profiling in 120 Stable Renal Allograft Recipients
C0 (ng/mL) C2 (ng/mL) AUCcalc (ng 䡠 h/mL) CsA dose (mg/kg)
Low Absorbers (C2/C0 ⬍3.6)
Intermediate Absorbers
High Absorbers (C2/C0 ⬎7.6)
120 ⫾ 53 346 ⫾ 130 3072 ⫾ 822 2.7 ⫾ 1.0
106 ⫾ 30 565 ⫾ 162 3418 ⫾ 649 2.6 ⫾ 0.8
77 ⫾ 20 705 ⫾ 185 3428 ⫾ 601 2.9 ⫾ 0.6
patients) and a group of high absorbers (C2/C0 ⬎7.6; 13.3% of patients). Most patients showed intermediate absorption profiles (74.2%). The mean values for C0, C2, AUC, and CsA dose in these different groups are shown in Table 1. Interestingly, high absorbers had lower trough levels than the other patients, but higher C2 levels and higher AUC; the group of low absorbers had the highest trough levels; but, compared with the other allograft recipients, low total drug exposure. There was no significant difference in CsA dose between the groups. DISCUSSION
Limited sampling strategies using a small number of blood samples to predict AUC, and therefore total drug exposure, have improved pharmacokinetic monitoring of CsA but are still inconvenient in clinical practice. The sampling of C2 values in 120 renal allograft recipients showed that monitoring C2 levels alone in stable renal allograft recipients is practical on an outpatient basis. C2 values are a good predictor of AUC, but trough levels reflect drug exposure to
a lesser extent. Repeated determinations of C0 and C2 levels showed a better coefficient of variation for C2 than for C0. Thus, drug monitoring using C2 levels in transplant patients provides a more accurate and reliable measure of drug exposure in the individual patient. The mean AUC and C2 levels in our long-term, clinically stable patient population were lower than those reported elsewhere.9 Close clinical follow-up will help to establish a therapeutic window for patients on long-term CyA therapy, which seems to be lower than previously anticipated. There were different absorption profiles among the patients, which reflects the variable pharmacokinetics of cyclosporine. Differences between low and high absorbers require further investigation.
REFERENCES 1. Kahan BD, Grevel J: Transplantation 46:631, 1988 2. Kaiske BL, Heim-Duthoy K, Rao KV, et al: Transplantation 46:716, 1988 3. Meyer MM, Muner M, Udeaja J, et al: J Am Soc Nephrol 4:1306, 1993 4. Kahan BD, Welsh M, Rutzky LP: Ther Drug Monit 17:621, 1995 5. David OJ, Johnston A: Ther Drug Monit 23:100, 2001 6. Keown P, Landsberg D, Halloran P, et al: Transplantation 62:1744, 1996 7. Gaspari F, Perico N, Signorini O, et al: Kidney Int 54:2146, 1998 8. Cole E, et al: Am J Transplant I(suppl 1):386, 2001 9. Levy GA: BioDrugs 15:279, 2001
T
HE INTRODUCTION of the immunosuppressive agent cyclosporine (CsA) into clinical practice was a major advance in the prevention and treatment of allograft rejection. However, clinicians soon came to realize the problems associated with dosing of CsA because of the narrow therapeutic window that allows adequate T-cell immunosuppression with minimum risk of side effects. Hypertension and renal dysfunction are common in allograft recipients, and nephrotoxicity secondary to CsA may progress toward end-stage renal failure. The highly variable pharmacokinetics1 have made therapeutic drug monitoring an indispensable tool for management of CsA therapy. By convention, monitoring became targeted to trough level (C0), which is still widely used to guide dose adjustments, although it has been shown that C0 values correlate poorly with total drug exposure and with clinical events in patients after organ transplantation. Although the introduction of the current CsA formulation (Neoral) has led to improved absorption and reduced pharmacokinetic variability, pharmacokinetic studies have shown that the area under the concentration–time curve (AUC) is a more sensitive predictor of acute and chronic rejection, graft survival rate, and nephrotoxicity.2– 4 However, conventional methods of measuring AUC require multiple samples and are therefore inconvenient in clinical practice. In additional studies it was demonstrated that, by using a limited sample strategy (LSS), AUC monitoring can be simplified for use in a routine clinical setting.5 The use of a small number of blood samples collected at specific timepoints provides the basis for estimating the real AUC. Several timepoints have been suggested for AUC prediction; most investigators have used two-point combinations. In particular, sampling times within the first 4 hours have been shown to be accurate, and a gap of 2 hours between the two points has been demonstrated to be compulsory for reliable predictions.5 The sampling of C0 and CsA concentrations at 2 hours postdose (C2) has been shown to be an accurate method of estimating AUC.6,7 As studies in kidney allograft recipients have shown, it seems that C2 alone is also sufficient for prediction of clinical outcome.8 However, there are only limited data for the required C2 levels in stable renal allograft recipients beyond the first 3 months after transplantation. This study
therefore aimed to generate a therapeutic window for C2 values in clinical practice. PATIENTS AND METHODS For method validation full ten-point CsA kinetics were performed in 24 stable patients. In 120 consecutive patients we determined 200 C0 and C2 levels. All patients (age 51.3 ⫾ 12 years, 62.5% male) were on stable Neoral (2.6 ⫾ 0.8 mg/kg per day) medication at 85 ⫾ 59 months after transplantation. In 49 patients, trough levels and C2 values were repeated during the next visit without dose change. All CsA concentrations were measured using a specific monoclonal antibody (EMIT assay, Dade–Behring). Area under the curve (AUC) was calculated using the linear trapezoidal rule and according to a standard formula for two-point AUC (990 ⫹ 10.74 ⴱ C0 ⫹ 2.28 ⴱ C2).
RESULTS
In the 24 full ten-point kinetics there was good correlation between measured ten-point AUC and calculated two-point AUC (r ⫽ .89). C0 showed a correlation with ten-point AUC of r ⫽ .77, which was weaker than the observed correlation of C2 with ten-point AUC (r ⫽ .85). The mean C0 in 120 long-term patients was 104 ⫾ 34 ng/mL, and C2 was 557 ⫾ 185 ng/mL. The mean calculated AUC was 3376 ⫾ 668 ng 䡠 h/mL. Ten percent of the calculated AUC values were ⬍2500 ng 䡠 h/mL, and 16% were ⬎4000 ng 䡠 h/ mL. We found a weak correlation between C0 and C2 (r ⫽ .44). CsA dose did not correlate with AUC, C0, or C2. Repeated determinations (n ⫽ 49) of C0 values showed a correlation of r ⫽ .55; coefficient of variation was 21%. Correlation of repeated C2 values gave better results (r ⫽ .75; coefficient of variation 17%). In the 120 stable renal allograft recipients the mean increase of C0 to C2 was by a factor of 5.6 ⫾ 2.0. Different absorption profiles could be observed in these patients: there was a group of low absorbers (C2/C0 ⬍3.6; 12.5% of From the Departments of Nephrology (G.E., F.D., L.F., T.B., H.-H.N., K.B.) and Clinical Pharmacology (I.M.), Humboldt University, Berlin, Germany. Address reprint requests to Dr G. Einecke, Department of Nephrology, Charite´, Humboldt University, Schumannstr 20121, 10098 Berlin, Germany.
0041-1345/01/$–see front matter PII S0041-1345(01)02322-3
© 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
3102
Transplantation Proceedings, 33, 3102–3103 (2001)
OPTIMIZING NEORAL MONITORING
3103
Table 1. Absorption Profiling in 120 Stable Renal Allograft Recipients
C0 (ng/mL) C2 (ng/mL) AUCcalc (ng 䡠 h/mL) CsA dose (mg/kg)
Low Absorbers (C2/C0 ⬍3.6)
Intermediate Absorbers
High Absorbers (C2/C0 ⬎7.6)
120 ⫾ 53 346 ⫾ 130 3072 ⫾ 822 2.7 ⫾ 1.0
106 ⫾ 30 565 ⫾ 162 3418 ⫾ 649 2.6 ⫾ 0.8
77 ⫾ 20 705 ⫾ 185 3428 ⫾ 601 2.9 ⫾ 0.6
patients) and a group of high absorbers (C2/C0 ⬎7.6; 13.3% of patients). Most patients showed intermediate absorption profiles (74.2%). The mean values for C0, C2, AUC, and CsA dose in these different groups are shown in Table 1. Interestingly, high absorbers had lower trough levels than the other patients, but higher C2 levels and higher AUC; the group of low absorbers had the highest trough levels; but, compared with the other allograft recipients, low total drug exposure. There was no significant difference in CsA dose between the groups. DISCUSSION
Limited sampling strategies using a small number of blood samples to predict AUC, and therefore total drug exposure, have improved pharmacokinetic monitoring of CsA but are still inconvenient in clinical practice. The sampling of C2 values in 120 renal allograft recipients showed that monitoring C2 levels alone in stable renal allograft recipients is practical on an outpatient basis. C2 values are a good predictor of AUC, but trough levels reflect drug exposure to
a lesser extent. Repeated determinations of C0 and C2 levels showed a better coefficient of variation for C2 than for C0. Thus, drug monitoring using C2 levels in transplant patients provides a more accurate and reliable measure of drug exposure in the individual patient. The mean AUC and C2 levels in our long-term, clinically stable patient population were lower than those reported elsewhere.9 Close clinical follow-up will help to establish a therapeutic window for patients on long-term CyA therapy, which seems to be lower than previously anticipated. There were different absorption profiles among the patients, which reflects the variable pharmacokinetics of cyclosporine. Differences between low and high absorbers require further investigation.
REFERENCES 1. Kahan BD, Grevel J: Transplantation 46:631, 1988 2. Kaiske BL, Heim-Duthoy K, Rao KV, et al: Transplantation 46:716, 1988 3. Meyer MM, Muner M, Udeaja J, et al: J Am Soc Nephrol 4:1306, 1993 4. Kahan BD, Welsh M, Rutzky LP: Ther Drug Monit 17:621, 1995 5. David OJ, Johnston A: Ther Drug Monit 23:100, 2001 6. Keown P, Landsberg D, Halloran P, et al: Transplantation 62:1744, 1996 7. Gaspari F, Perico N, Signorini O, et al: Kidney Int 54:2146, 1998 8. Cole E, et al: Am J Transplant I(suppl 1):386, 2001 9. Levy GA: BioDrugs 15:279, 2001