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Importance of cyclosporine pharmacokinetics to clinical outcomes after liver transplantation
Importance of Cyclosporine Pharmacokinetics to Clinical Outcomes After Liver Transplantation Canadian Liver Transplant Study Group
T
HE USE of Sandimmune in liver transplant recipients is associated with marked pharmacokinetic variability with large variations in area under the curve (AUC), Cmax, and Tmax.1 To overcome this variability, intravenous (IV) cyclosporine (CyA) has been used either alone or in combination with Sandimmune especially in the early postoperative period. Despite maintaining a CyA concentration of approximately 500 or 600 ng/mL which is associated with a high AUC, the incidence of acute cellular rejection remained high at 60% to 70%. Many patients developed severe neurotoxic and nephrotoxic complications. These clinical data suggested that although AUC may be important in predicting freedom from rejection,2 the use of a continuous infusion of CyA which yields a high AUC fails to protect from rejection.
Therefore, other parameters associated with AUC may be important in producing a beneficial effect. The introduction of Neoral has corrected many of the problems associated with the use of Sandimmune including reduction in intrapatient and interpatient variability; dependence on bile and food for absorption; and the need for intravenous CyA in the early postoperative period.3 A prospective randomized, double-blind multicentered From the University of Toronto, The Toronto Hospital, Ontario, Canada. Address reprint requests to Dr G.A. Levy, The Toronto Hospital, Norman-Urquhart 10-151, 621 University Avenue, Toronto, Ontario, M5G 2C4.
Fig 1. Incidence of rejection vs Cmax at day 10 in liver transplant patients. Data are from the NOF-8 Canadian Study. 0041-1345/98/$19.00 PII S0041-1345(98)00446-1
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1826
Transplantation Proceedings, 30, 1826–1827 (1998)
IMPORTANCE OF CYA PHARMACOKINETICS
1827
Table 1. Correlations Between Pharmacokinetic Parameters and Graft Rejection During the First Month After Transplantation Neoral Parameter
Wk
Quartile
n/N
%
Cmax Cmax Cmax Cmax AUC AUC AUC AUC CO CO CO CO
2 2 2 2 2 2 2 2 2 2 2 2
1 2 3 4 1 2 3 4 1 2 3 4
10/14 8/19 8/23 9/29 9/13 8/18 9/25 9/29 11/21 8/20 7/23 9/21
71.4 42.1 34.8 31/0 69.2 44.4 36.0 31.0 52.4 40.4 30.4 42.9
trial was undertaken in Canada to compare two treatment groups in terms of percentage of patients with one or more episodes of rejection.4 Secondary end points included requirement for intravenous CyA, ease of achieving and maintaining therapeutic CyA blood levels, and correlation between CyA pharmacokinetics and clinical events. METHODS AND RESULTS One hundred and eighty eight patients, all of whom received a primary liver transplant, were randomized to receive either Sandimmune or Neoral (10 mg/kg/d) in combination with intravenous CyA. Patients receiving Neoral achieved target blood levels (Cmin) sooner than the Sandimmune patients (P , .05). More patients in the Sandimmune group had to discontinue treatment due to failure to achieve target levels (P , .03). The median dose of drug was significantly lower in patients treated with Neoral (7.5 mg/kg/d) than in those treated with Sandimmune (9 mg/kg/d) (P , .001). The safety and tolerability profiles were similar in both groups. Graft and patient survival rates were excellent (90%). Rejection rates in Neoral-treated patients who achieved Cmax values greater than 800 ng/mL or AUC greater than 3300 mcg.h/h were 28.6% and 33.3%, respectively (Fig 1). A similar relationship was seen in patients who received Sandimmune, however, fewer patients receiving Sandimmune as compared with Neoral achieved high Cmax and AUC. In patients receiving Neoral, C-2 proved to be an excellent surrogate marker of AUC (r2 5 .93) whereas the relationship of C-2 to AUC in the Sandimmune group was not as good (r2 5 .73). No relationship between C-0 (trough level) and freedom from rejection was seen in either group, even with C-0 reaching 450 ng/mL (Table 1). When the data sets were divided into four quartiles of Cmin ranges, there was no trend towards freedom from acute rejection and increase in Cmin values. Conversely, when Cmax quartiles were examined for the incidence, there was a significant reduction in the incidence of rejection in patients who achieved higher Cmax. This relationship was similar for both Sandimmune and Neoral, although it was only significant for the patients who received Neoral. On further examination of the data, there was a strong correlation between Cmax and C-2. Furthermore, there was also a strong correlation between C-2 and AUC (r 5 .93), confirming the
Sandimmune P
.019
.026
.417
n/N
%
15/29 8/23 7/19 3/13 17/30 6/24 7/17 3/13 9/22 7/22 9/19 8/21
51.7 34.8 36.8 23.1 56.7 25.0 41.2 23.1 40.9 31.8 47.4 38.1
P
.087
.060
.894
utility of C-2 as a surrogate monitoring tool for CyA therapeutic drug monitoring. More recently, a small open-labeled prospective trial at the University of Toronto in six liver transplant patients examined the usefulness of monitoring C-2 levels of Neoral. C-2 levels of 800 to 1200 ng/mL were achieved by giving 15 mg/kg, although some patients did require 20 mg/kg to achieve the target levels. C-2 target levels were achieved within 48 hours with a mean dosage requirement of 13.5 mg/kg/d (days 1 to 5 posttransplant), 10.6 mg/kg/d (days 6 to 10 posttransplant), and 8.7 mg/kg/d (days 13 to 20 posttransplant). There was a slight increase in the incidence of nephrotoxicity at 6 months posttransplant (glomerular filtration rate [GFR] fell from 78 mmol/L to 72 mmol/L). Some patients complained of warmth (especially females) around the time of Cmax, but no other serious neurologic sequelae were observed. All patients underwent protocol biopsies and only one patient was found to have cellular rejection at 6 months (15%).
CONCLUSIONS
Thus, these studies collectively demonstrate that induction immunosuppression with Neoral is more effective than with Sandimmune, as demonstrated by a lower incidence of acute rejection with no additional toxicity. However, these results suggest that for the full beneficial effects, early measurements of Cmax and/or AUC will be required. However, C-2 may prove to be an excellent surrogate marker for these two pharmacokinetic parameters. In addition, these results appear to open new avenues concerning the ways in which patients are managed long term to further optimize the use of CyA. REFERENCES 1. Freeman D, Grant D, Levy GA: Ther Drug Monit 17:213, 1995 2. Lindholm A, Henricsson S, Lind M, et al: Eur J Clin Pharmacol 34:461, 1988 3. Vonderscher J, Meinzer A: Transplant Proc 26:2925, 1994 4. Levy G, Altraif I, Rezieg M, et al: Transplant Proc 26:3184, 1994
T
HE USE of Sandimmune in liver transplant recipients is associated with marked pharmacokinetic variability with large variations in area under the curve (AUC), Cmax, and Tmax.1 To overcome this variability, intravenous (IV) cyclosporine (CyA) has been used either alone or in combination with Sandimmune especially in the early postoperative period. Despite maintaining a CyA concentration of approximately 500 or 600 ng/mL which is associated with a high AUC, the incidence of acute cellular rejection remained high at 60% to 70%. Many patients developed severe neurotoxic and nephrotoxic complications. These clinical data suggested that although AUC may be important in predicting freedom from rejection,2 the use of a continuous infusion of CyA which yields a high AUC fails to protect from rejection.
Therefore, other parameters associated with AUC may be important in producing a beneficial effect. The introduction of Neoral has corrected many of the problems associated with the use of Sandimmune including reduction in intrapatient and interpatient variability; dependence on bile and food for absorption; and the need for intravenous CyA in the early postoperative period.3 A prospective randomized, double-blind multicentered From the University of Toronto, The Toronto Hospital, Ontario, Canada. Address reprint requests to Dr G.A. Levy, The Toronto Hospital, Norman-Urquhart 10-151, 621 University Avenue, Toronto, Ontario, M5G 2C4.
Fig 1. Incidence of rejection vs Cmax at day 10 in liver transplant patients. Data are from the NOF-8 Canadian Study. 0041-1345/98/$19.00 PII S0041-1345(98)00446-1
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1826
Transplantation Proceedings, 30, 1826–1827 (1998)
IMPORTANCE OF CYA PHARMACOKINETICS
1827
Table 1. Correlations Between Pharmacokinetic Parameters and Graft Rejection During the First Month After Transplantation Neoral Parameter
Wk
Quartile
n/N
%
Cmax Cmax Cmax Cmax AUC AUC AUC AUC CO CO CO CO
2 2 2 2 2 2 2 2 2 2 2 2
1 2 3 4 1 2 3 4 1 2 3 4
10/14 8/19 8/23 9/29 9/13 8/18 9/25 9/29 11/21 8/20 7/23 9/21
71.4 42.1 34.8 31/0 69.2 44.4 36.0 31.0 52.4 40.4 30.4 42.9
trial was undertaken in Canada to compare two treatment groups in terms of percentage of patients with one or more episodes of rejection.4 Secondary end points included requirement for intravenous CyA, ease of achieving and maintaining therapeutic CyA blood levels, and correlation between CyA pharmacokinetics and clinical events. METHODS AND RESULTS One hundred and eighty eight patients, all of whom received a primary liver transplant, were randomized to receive either Sandimmune or Neoral (10 mg/kg/d) in combination with intravenous CyA. Patients receiving Neoral achieved target blood levels (Cmin) sooner than the Sandimmune patients (P , .05). More patients in the Sandimmune group had to discontinue treatment due to failure to achieve target levels (P , .03). The median dose of drug was significantly lower in patients treated with Neoral (7.5 mg/kg/d) than in those treated with Sandimmune (9 mg/kg/d) (P , .001). The safety and tolerability profiles were similar in both groups. Graft and patient survival rates were excellent (90%). Rejection rates in Neoral-treated patients who achieved Cmax values greater than 800 ng/mL or AUC greater than 3300 mcg.h/h were 28.6% and 33.3%, respectively (Fig 1). A similar relationship was seen in patients who received Sandimmune, however, fewer patients receiving Sandimmune as compared with Neoral achieved high Cmax and AUC. In patients receiving Neoral, C-2 proved to be an excellent surrogate marker of AUC (r2 5 .93) whereas the relationship of C-2 to AUC in the Sandimmune group was not as good (r2 5 .73). No relationship between C-0 (trough level) and freedom from rejection was seen in either group, even with C-0 reaching 450 ng/mL (Table 1). When the data sets were divided into four quartiles of Cmin ranges, there was no trend towards freedom from acute rejection and increase in Cmin values. Conversely, when Cmax quartiles were examined for the incidence, there was a significant reduction in the incidence of rejection in patients who achieved higher Cmax. This relationship was similar for both Sandimmune and Neoral, although it was only significant for the patients who received Neoral. On further examination of the data, there was a strong correlation between Cmax and C-2. Furthermore, there was also a strong correlation between C-2 and AUC (r 5 .93), confirming the
Sandimmune P
.019
.026
.417
n/N
%
15/29 8/23 7/19 3/13 17/30 6/24 7/17 3/13 9/22 7/22 9/19 8/21
51.7 34.8 36.8 23.1 56.7 25.0 41.2 23.1 40.9 31.8 47.4 38.1
P
.087
.060
.894
utility of C-2 as a surrogate monitoring tool for CyA therapeutic drug monitoring. More recently, a small open-labeled prospective trial at the University of Toronto in six liver transplant patients examined the usefulness of monitoring C-2 levels of Neoral. C-2 levels of 800 to 1200 ng/mL were achieved by giving 15 mg/kg, although some patients did require 20 mg/kg to achieve the target levels. C-2 target levels were achieved within 48 hours with a mean dosage requirement of 13.5 mg/kg/d (days 1 to 5 posttransplant), 10.6 mg/kg/d (days 6 to 10 posttransplant), and 8.7 mg/kg/d (days 13 to 20 posttransplant). There was a slight increase in the incidence of nephrotoxicity at 6 months posttransplant (glomerular filtration rate [GFR] fell from 78 mmol/L to 72 mmol/L). Some patients complained of warmth (especially females) around the time of Cmax, but no other serious neurologic sequelae were observed. All patients underwent protocol biopsies and only one patient was found to have cellular rejection at 6 months (15%).
CONCLUSIONS
Thus, these studies collectively demonstrate that induction immunosuppression with Neoral is more effective than with Sandimmune, as demonstrated by a lower incidence of acute rejection with no additional toxicity. However, these results suggest that for the full beneficial effects, early measurements of Cmax and/or AUC will be required. However, C-2 may prove to be an excellent surrogate marker for these two pharmacokinetic parameters. In addition, these results appear to open new avenues concerning the ways in which patients are managed long term to further optimize the use of CyA. REFERENCES 1. Freeman D, Grant D, Levy GA: Ther Drug Monit 17:213, 1995 2. Lindholm A, Henricsson S, Lind M, et al: Eur J Clin Pharmacol 34:461, 1988 3. Vonderscher J, Meinzer A: Transplant Proc 26:2925, 1994 4. Levy G, Altraif I, Rezieg M, et al: Transplant Proc 26:3184, 1994