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Impact of cyclosporine dosing frequency on graft function and survival after the conversion from sandimmun to neoral in stable kidney transplanted patients
Impact of Cyclosporine Dosing Frequency on Graft Function and Survival After the Conversion From Sandimmun to Neoral in Stable Kidney Transplanted Patients E.L.M. Sampaio, S.I. Park, C.R. Felipe, H.T. Silva Jr, and J.O.M. Pestana
S
ANDIMMUN (SIM), the oil-based cyclosporine formulation, has been used to prevent acute rejection after kidney transplantation for more than 20 years. In the first clinical trials cyclosporine was administered as single daily doses and adjustments were performed according to rigid and predetermined algorithms, on occurrence of side effects, or to assure long-term compliance.1– 6 The introduction of therapeutic drug monitoring offered a better strategy to improve the therapeutic use of cyclosporine.7–9 Kahan et al proposed that dosing frequency should be predicted by determining drug elimination rates in the context of full pharmacokinetic studies and suggested that cyclosporine should be dosed every two half-lives due to its narrow therapeutic index and the relationship between trough levels and toxic complications.8 Savoldi et al, however, demonstrated that with significantly lower doses the administration of cyclosporine twice daily produced similar trough concentrations and efficacy outcomes although higher incidence of hepatotoxicities and nefrotoxicities were observed during the first month.10 The so-called triple therapy consisted of cyclosporine, azathioprine, and prednisone, which gained wide acceptance among transplantation centers, consisted of using lower cyclosporine doses administered twice daily.11,12 Wrenshall et al described an increase in the incidence of late acute rejection after switching patients from BID to QD schedules 1 year after transplantation. In this study, however, whole blood concentrations in those patients were less than 50 ng/mL.6 Hsieh et al successfully switched 17 patients who had relatively high cyclosporine trough concentrations while on a BID schedule after 1 year of transplantation.13 Difficulties in establishing dosing frequency for the oil-based cyclosporine formulation is related to its considerable interindividual and intraindividual pharmacokinetic variability after transplantation, mainly due to differences in the rate and extent of its absorption.8,14,15 Therefore, it is not surprising that many patients benefited from individualized dosing schedules, especially those with cyclosporine-associated toxic effects.8,16 The new microemulsion formulation of cyclosporine (NEO) improved the absorption characteristics of cyclosporine. Not only the extent of absorption improved, mainly in the previous poor absorbers, but also the rate so that
peak concentrations are consistently achieved earlier after drug administration.17–21 Moreover, interpatient and intrapatient variability was reduced, facilitating therapeutic drug monitoring and perhaps improving long-term graft survival due to significantly less fluctuation in cyclosporine blood concentration.22–24 NEO was developed to be given in a twice a day schedule, supported by its more predictable and less variable pharmacokinetics.25,26 Based on the pharmacokinetic advantages of NEO, many studies addressed the efficacy and safety of the conversion from SIM to NEO. First, well-designed conversion trials demonstrated that the 1:1 conversion ratio was safe as long as therapeutic drug monitoring was implemented to correct for significant improvement in cyclosporine absorption, preventing the emergence of toxic side effects.27–30 There were no established guidelines, however, to convert those patients on single daily doses of SIM. Vasala et al, in a transplant population with stable and excellent graft function (creatinine ⫽ 124 ⫾ 27 mol/L), reported a parallel increase in serum creatinine and cyclosporine exposures, measured either by trough or average cyclosporine concentrations, in 55.6% of the patients converted from once a day SIM to twice-daily NEO. They suggested that the lack of drug holiday (decrease of cyclosporine concentrations over a 24-hour dosing interval31) after conversion to twice-daily NEO could have been involved and that conversion to once daily NEO could have prevented this effect.32 Later, the same group conducted a conversion study from SIM to NEO in 24 stable kidney transplant patients with underlying liver disease receiving single daily doses of cyclosporine. Significant increases in cyclosporine blood concentrations were observed and dose reductions were necessary to avert nephrotoxicity during a 4-week follow-up.33 In the patient cohort presented here, the most frequent cause to switch from twice-daily to single-daily SIM dosing was unsatisfactory graft function with clinical and/or histoFrom the Nephrology Division, Hospital do Rim e Hipertensa˜o, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil. Address reprint requests to Helio Tedesco Silva, Jr, MD, Nephrology Division, Hospital do Rim e Hipertensa˜o, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil 04038-002. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03659-X
Transplantation Proceedings, 34, 3153–3161 (2002)
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logical signs of cyclosporine toxicity. Therefore, our major concern was that the conversion of these patients from once a day SIM to a twice-daily NEO regimen would increase their cyclosporine exposure and would likely compromise graft function.29,34 Furthermore, studies also have shown that conversion should be very cautious in patients with graft dysfunction, in which a 1:1 direct conversion could lead to worsening of graft function.29,35,36 We present here the short-term and long-term impacts of the conversion from once-daily SIM to once-daily NEO on graft function, and on graft and patient survival, as well as detailed analysis of cyclosporine dose and whole blood concentrations measured during a 6-year follow-up period. METHODS Population Between October 9, 1995 and November 13, 1997, 182 kidney transplant recipients receiving cyclosporine-based immunosuppressive therapy were converted from SIM to NEO at our institution. All patients were receiving cyclosporine-based immunosuppressive therapy since the first day after the transplantation. At the time of conversion, 119 (65.4%) patients were receiving cyclosporine, azathioprine, and prednisone; 36 (19.8%) were receiving cyclosporine and Prednisone; 17 (9.3%) were receiving cyclosporine and azathioprine; and 10 (5.5%) were receiving cyclosporine alone. Eighty-two patients (45%) were receiving SIM in a once-daily schedule (QD) and 100 (55%) in a twice-daily (BID) schedule at the time of conversion. This was a retrospective comparative study of two treatment schedules after the conversion from SIM to NEO in stable kidney transplanted patients.
Conversion Protocol The decision to switch from SIM to NEO was left at the discretion of the patients own physicians. All patients were informed of the risks and benefits before the conversion. Minimum eligibility criteria were stable kidney allograft function and lack of clinical or biopsy-confirmed acute rejection within the last 3 months. Eligible patients were switched from SIM to NEO using a 1:1 ratio. Cyclosporine blood concentrations were monitored after conversion and adjustments were made for safety and tolerability. For the purpose of this retrospective analysis, we only included patients who met the following criteria: (1) patients who were receiving the same SIM schedule (BID or QD) in the last 3 visits prior to conversion; (2) patients who were converted to NEO following the same SIM treatment schedule (BID 3 BID; QD 3 QD); and (3) patients who were kept in the same NEO schedule for at least 1 year of follow-up. Therefore, for this analysis we selected 141 patients, 53 on a QD (group 1, G1) and 88 on a BID SIM schedule (group 2, G2). The majority of patients excluded from G1 were converted from QD to BID cyclosporine schedule.
Follow-Up Parameters Because patients had a wide range of posttransplantation follow-up time, mean times of the three pre-conversion run-in visits and four post-conversion follow-up visits during the first year were ⫺ 0.7 ⫾ 0.4, ⫺ 0.4 ⫾ 0.2, and ⫺ 0.2 ⫾ 0.1, and 0.1 ⫾ 0.05, 0.2 ⫾ 0.01, 0.4 ⫾ 0.1, and 1 ⫾ 0.2 years, respectively. Thereafter, follow-up parameters were obtained every year up to 5 years after the conversion. There were no significant differences comparing mean
SAMPAIO, PARK, FELIPE ET AL visit times of G1 versus G2 (not shown). At each visit weight, blood pressure, number of antihypertensive drugs, dose of azathioprine and prednisone, dose and blood concentrations of cyclosporine, and creatinine plasma levels were obtained. Because patients had stable but a relatively wide range of graft function (creatinine levels from 0.7 to 3.5 mg/dL at first pre-conversion visit) and to analyze whether the conversion produced a deterioration of graft function, either in a QD or BID schedule, for each patient graft function also was analyzed using the 1/creatinine versus time strategy. For this purpose, all creatinine values between the first and the last study visit were included (at least seven time points were used for each patient). The slopes of the regression lines were compared between the two groups. Cyclosporine blood concentrations were measured before the morning drug administration, 24 (C24) and 12 (C12) hours after the last dose in groups G1 and G2, respectively. Inter-individual and intraindividual variability was expressed as percent coefficient of variation (%CV ⫽ standard deviation/mean). Cyclosporine whole blood concentrations were determined with monoclonal antibody using the fluorescence polarization immunoassay kit (Abbott Laboratories, Chicago, Ill, USA), according to the manufacture’s directions. Performance was assessed on the basis of a three-point quality control concentration range of low (70 ng/mL), intermediate (300 ng/mL), and high (600 ng/mL) concentrations, and the limit of quantification of the assay was 25 ng/mL.
Graft Dysfunction Due to the large period of observation, from October 9, 1995 to March 31, 2002, it was difficult to establish uniform criteria for acute rejection. Therefore, in this retrospective analysis, preconversion acute rejection episodes were defined as a graft dysfunction, which responded to a full treatment with steroids or were biopsy-confirmed. After conversion, graft dysfunction was defined as a 20% or more increase in creatinine values compared to the last value before conversion. Patients with graft dysfunction were followed closely with repeated measurements of serum creatinine levels, cyclosporine blood levels, and ultrasound evaluations. If cyclosporine blood level was equal or higher than the last value before conversion, cyclosporine dose was decreased until a comparable or a lower blood level was observed. At the discretion of the physician a core graft biopsy was performed based on his or her clinical judgment. If no features of acute rejection were observed, then a further reduction of cyclosporine dose was done in an attempt to bring the creatinine level back to the previous value before conversion. In case of biopsy-proven acute rejection, a full course of methylprednisolone was administered. Another biopsy was performed if no or partial response to steroid therapy was observed.
Patient and Graft Survival All patients were included in the analysis so as to assess patient and graft survival in each entire group. Graft survival was determined noting grafts losses and patient deaths. Patients who were lost to follow-up, had a change in either treatment schedules (from BID to QD or vice versa), or who were withdrawn from cyclosporine were not included in the analysis.
Statistical Analysis Demographic characteristics were analyzed by two-sided unpaired Student t tests (continuous variables) and by chi-square tests (categorical variables). Summary statistics were expressed as mean and standard deviation, or frequencies or median and range,
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Table 1. Demographic Characteristics*
N Age (y)** Weight (kg)** Gender, N (%) Male Female Ethnicity, N (%) White Mulatto Black Others Cause of endostage renal disease, N (%) Chronic glomerulonephritis Hypertension Diabetes melitus Polycistic kidney disease Unknown origin Others Donor source**, N (%) Living donor Cadaver donor Retransplantation, N (%) Cold ischemic time (h)
Delayed graft function**, N (%) Acute rejection**, N (%) Living donor Cadaver donor Imunnosupression, N (%) Cyclosporine, azathioprine, and prednisone Cyclosporine and azathioprine Cyclosporine and prednisone CSA Cyclosporine Conversion (mo)**
Total
Group 1
Group 2
141 31.9 ⫾ 13.7 (5.0 – 62.0) 61.1 ⫾ 15.6 (19.4 –101.8)
53 36.9 ⫾ 10.8 (17.0 – 62.0) 64.9 ⫾ 11.5 (47.0 –96.7)
88 29.0 ⫾ 14.4 (5.0 –58.0) 58.8 ⫾ 17.3 (19.4 –101.8)
81 (57.4) 60 (42.6)
36 (67.9) 17 (32.1)
45 (51.1) 43 (48.9)
83 (58.9) 41 (29.1) 11 (7.8) 6 (4.2)
29 (54.7) 16 (30.2) 5 (9.4) 3 (5.7)
54 (61.4) 25 (28.4) 6 (6.8) 3 (3.4)
70 (49.6) 7 (5.0) 4 (2.8) 4 (2.8) 27 (19.2) 29 (20.6)
26 (49.1) 5 (9.4) 1 (1.9) 2 (3.8) 12 (22.6) 7 (13.2)
44 (50.0) 2 (2.3) 3 (3.4) 2 (2.3) 15 (17.0) 22 (25.0)
47 (33.3) 94 (66.7) 2 (1.4) 26.5 ⫾ 8.1 (5.0 – 47.0) N ⫽ 91 34 (37.4) 83 (58.9) 22 (46.8) 61 (64.9)
26 (49.1) 27 (50.9) 2 (3.8) 24.7 ⫾ 9.0 (12.0 – 47.0) N ⫽ 26 15 (57.7) 38 (71.7) 16 (30.2) 22 (41.5)
21 (23.9) 67 (76.1) 0 (0.0) 27.2 ⫾ 8.1 (5.0 – 43.0) N ⫽ 65 19 (29.2) 45 (51.1) 6 (6.8) 39 (44.3)
97 (68.8)
37 (69.8)
60 (68.2)
11 (7.8) 26 (18.4) 7 (5.0) 51.3 ⫾ 26.3 (6 –134)
4 (7.5) 10 (18.9) 2 (3.8) 59.7 ⫾ 23.3 (17–133)
7 (8.0) 16 (18.1) 5 (5.7) 46.3 ⫾ 26.8 (6 –134)
*Mean ⫾ standard deviation, (range); **P ⬍ .05 G1 vs G2.
respectively. General linear model (GLM) for repeated measures was used to compare weight, blood pressure, number of antihypertensive drugs, dose of azathioprine and prednisone, and creatinine plasma levels, with visit and group used as sources of variation before and after conversion. Least squares linear regressions were used to calculate the evolution of 1/creatinine versus time, and the slopes obtained from each patient of G1 and G2 groups were compared using a two-sided unpaired Student t test. Patient and graft survival were calculated using the Kaplan-Meier method and differences between the two groups were identified using the log-rank test. Statistical analysis was done using SPSS 7.5 software (SPSS Inc.). Differences were considered significant at P ⬍ .05.
RESULTS Demographic Characteristics
The demographic characteristics are shown in Table 1. Mean age was 31.9 ⫾ 13.7 years and mean weight was 61.1
⫾ 15.6 kg. Of the total 57.4% were men and 58.9% were white. The majority of the patients (98.6%) were recipients of first kidney transplants. Recipients of cadaveric allografts (66.7%) had a mean cold ischemia time of 26.5 ⫾ 8.1 hours and 37.4% of them developed delayed graft function. Acute rejection rate was 58.9%, being 46.8% in living and 64.9% in cadaveric allograft recipients, respectively. At the time of conversion, 68.8% of the patients were receiving cyclosporine, azathioprine, and prednisone, 18.4% were receiving cyclosporine and prednisone, 7.8% were receiving cyclosporine and azathioprine, and 5% were receiving cyclosporine alone. Compared to G2, G1 showed older (36.9 ⫾ 10.8 vs 29 ⫾ 14.4 years; P ⫽ .001) and heavier (65 ⫾ 11.7 vs 58.5 ⫾ 16.8; P ⫽ .022) patients, higher proportion of living allograft recipients (49.1% vs 23.9%; P ⫽ .003), higher incidence of delayed graft function (57.7% vs 29.2%; P ⫽
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SAMPAIO, PARK, FELIPE ET AL Table 2. Graft Function and Blood Pressure Control Before and After Conversion From SIM to NEO Follow-Up Time After
SIM
NEO
Systolic Blood Pressure (mm Hg)
Creatinine (mg/dL)
Conversion (y)
Transplantation (y)
⫺0.7 ⫺0.4 ⫺0.2 0.1 0.2 0.4 1.0 2.0 3.0 4.0 5.0
3.8 4.0 4.3 4.5 4.6 4.7 5.5 6.4 7.4 8.5 9.3
GLM** ⫺0.7 3 1.0
1.0 3 5.0
G1
G2
1.7 ⫾ 0.5 1.5 ⫾ 0.5 1.8 ⫾ 0.5 1.4 ⫾ 0.5 1.7 ⫾ 0.4 1.4 ⫾ 0.5 1.8 ⫾ 0.6 1.6 ⫾ 0.5 1.8 ⫾ 0.6 1.6 ⫾ 0.7 1.9 ⫾ 0.7 1.7 ⫾ 0.5 2.0 ⫾ 0.8 1.6 ⫾ 0.6 1.8 ⫾ 0.6 1.5 ⫾ 0.5 2.1 ⫾ 1.4 1.7 ⫾ 0.6 2.0 ⫾ 1.0 1.6 ⫾ 0.5 2.1 ⫾ 0.6 1.8 ⫾ 0.4 Within visits Between groups Within visits ⫻ groups Within visits Between groups Within visits ⫻ groups
Dyastolic Blood Pressure (mm Hg)
No. of Antihypertensive Drugs
P*
G1
G2
P*
G1
G2
P*
G1
G2
P*
.007 ⬍.001 .001 .011 .043 .027 .004 .024 .023 .005 .075 ⬍.001 .001 .566 ⬍.001 .236 .131
136 ⫾ 16 135 ⫾ 18 132 ⫾ 13 133 ⫾ 14 135 ⫾ 18 137 ⫾ 21 135 ⫾ 19 140 ⫾ 19 142 ⫾ 23 135 ⫾ 21 145 ⫾ 14
128 ⫾ 19 127 ⫾ 19 127 ⫾ 19 127 ⫾ 22 127 ⫾ 24 126 ⫾ 21 128 ⫾ 23 132 ⫾ 23 135 ⫾ 18 139 ⫾ 19 133 ⫾ 19
.013 .017 .067 .087 .028 .006 .069 .069 .070 .467 .075 .777 .006 .917 .474 .249 .609
88 ⫾ 9 89 ⫾ 14 87 ⫾ 12 85 ⫾ 11 86 ⫾ 12 89 ⫾ 20 88 ⫾ 12 90 ⫾ 13 88 ⫾ 11 85 ⫾ 13 92 ⫾ 11
86 ⫾ 13 84 ⫾ 14 82 ⫾ 15 83 ⫾ 15 83 ⫾ 16 82 ⫾ 14 82 ⫾ 16 85 ⫾ 16 85 ⫾ 12 86 ⫾ 12 84 ⫾ 9
.407 .028 .032 .304 .317 .020 .021 .049 .143 .522 .044 .023 .022 .523 .399 .142 .680
1.4 ⫾ 1.0 1.5 ⫾ 1.0 1.5 ⫾ 1.0 1.5 ⫾ 1.0 1.4 ⫾ 1.0 1.4 ⫾ 1.0 1.4 ⫾ 1.1 1.4 ⫾ 1.0 1.4 ⫾ 1.2 1.4 ⫾ 1.1 1.4 ⫾ 1.3
1.2 ⫾ 1.0 1.2 ⫾ 1.0 1.2 ⫾ 1.1 1.2 ⫾ 1.1 1.4 ⫾ 1.5 1.3 ⫾ 1.1 1.2 ⫾ 1.1 1.2 ⫾ 1.1 1.3 ⫾ 1.1 1.4 ⫾ 1.2 1.6 ⫾ 1.1
.282 .157 .080 .129 .804 .782 .276 .523 .520 .879 .759 .706 .273 .087 .002 .330 .278
*Independent sample Student t test (G1 vs G2). **General Linear Model for repeated measures (G1 vs G2).
.016), higher incidence of acute rejection (71.7% vs 51.1%; P ⫽ .025), and longer posttransplantation follow-up at the time of conversion (59.7 ⫾ 23.3 vs 46.3 ⫾ 26.8; P ⫽ .003). Patients in G1 were switched from BID to QD SIM schedule 11.6 ⫾ 16.6 months (0.3 to 80.2 months) after transplantation when mean creatinine values were 2.46 ⫾ 2 mg/dL (1.2 to 13 mg/dL). Therefore, at the time of conversion to NEO, patients were receiving QD SIM for a mean time of 50.6 ⫾ 27.2 months (range: 6 to 134 months). Follow-Up Parameters
During pre-conversion baseline visits up to 1 year after conversion to NEO, mean creatinine values increased in both groups (1.7 ⫾ 0.5 vs 2.0 ⫾ 0.8 mg/dL, G1; 1.4 ⫾ 0.5 vs 1.6 ⫾ 0.6 mg/dL, G2, within visits; P ⬍ .001, GLM for repeated measures, Table 2). Patients in G1 still showed higher mean creatinine values in all study visits compared to G2 (between groups; P ⫽ .001). Finally, patients in G1 showed similar a increment in creatinine values compared to patients in G2 (within visit group; P ⫽ .566). Blood pressure also was significantly higher among patients in G1 at any visit during the first year after conversion to NEO with no significant differences in the mean number of antihypertensive drugs. Overall, this data demonstrated that conversion from SIM to NEO was safe in a short-term follow-up, and that no significant differences in graft function or blood pressure control were found comparing patients on QD or BID NEO schedules. Extending the analysis from 1 to 5 years after conversion to NEO, the results were still very similar. There was a persistent and similar rate of increment in mean creatinine
values in both groups (2.0 ⫾ 0.8 vs 2.1 ⫾ 0.6 mg/dL, G1; 1.6 ⫾ 0.6 vs 1.8 ⫾ 0.4 mg/dL, G2, within visits; P ⬍ .001; between groups, P ⫽ .236; within visit group, P ⫽ .131), with no significant differences in blood pressure. The mean number of anti-hypertensive drugs used in G2 between 1 and 5 years after conversion increased significantly, however, from 1.2 ⫾ 1.1 vs 1.6 ⫾ 1.1 mg/dL (P ⫽ .002). Therefore, even after a long-term follow-up period, conversion from SIM to NEO was safe with no significant differences in graft function and blood pressure control comparing patients receiving QD or BID NEO schedules (Table 2). To confirm short-term and long-term safety and further determine whether the conversion from SIM to NEO in these two treatment schedules showed any differential detrimental effects on long-term graft function, the decrease in allograft function was compared by analyzing the slopes of the plots of 1/creatinine as a function of time elapsed after the first study visit in each group. Patients in G1 showed a slower rate of decline in graft function comparing mean slopes of each group during a 5-year follow-up (⫺0.00008 ⫾ 0.000015 vs ⫺0.00015 ⫾ 0.00020 [mg/dL]⫺1 per day; 95% confidence interval ⫽ 0.0000067 ⫺ 0.0001347; P ⫽ .031; Fig 1). The percentage of patients with worsening graft function, determined by a negative slope, was higher in G2 compared to G1 (87.5% vs 77%; P ⫽ .091). Immunosuppression
There were no statistically significant differences comparing mean values of azathioprine or prednisone doses during the follow-up period while patients were receiving SIM or NEO (data not shown). Mean cyclosporine doses were signifi-
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Fig 1. Slopes showing progression of allograft dysfunction over time using the least squares mean analysis (P ⫽ .031; G1 vs G2).
cantly higher in G2 compared to G1 up to 4 years of follow-up (Table 3). Compared to the first dose of NEO, doses of cyclosporine were equally reduced in both groups during the 5-year follow-up period (G1: 6, 8, 13, 16, and 26%; G2: 9, 16, 17, 22, and 30%). C24 concentrations in G1 were significantly lower compared to C12 concentrations in G2 only during the first 3 study visits, however, when patients were receiving SIM. After conversion to NEO, even receiving lower doses of cyclosporine, C24 levels in G1 were not different compared to C12 levels in G2 (Table 3; Fig 2). Dose-normalized cyclosporine concentrations were not different while patients were receiving SIM but were numerically higher in G1 compared to G2 in most of the visits after conversion to NEO (Table 3). Compared to SIM, percentage increases in dose-normalized cyclosporine
concentrations after conversion to NEO varied from 20% to 43% in G1 compared to ⫺7% to 18% in G2. While patients were receiving SIM, there were no significant differences comparing mean interindividual (G1: 59 ⫾ 13%; G2: 56 ⫾ 7%; P ⫽ .67) and intraindividual (G1: 40 ⫾ 25%; G2: 34 ⫾ 21%; P ⫽ .11) variability in dose⫽normalized cyclosporine blood concentrations, respectively. Similar results were obtained comparing mean interindividual (G1: 51 ⫾ 11%; G2: 53 ⫾ 6%; P ⫽ .69) and intraindividual (G1: 28 ⫾ 16%; G2: 32 ⫾ 20%; P ⫽ .23) variability after conversion to NEO. Decreases in interindividual and intraindividual variability were observed after conversion from SIM to NEO, reaching statistical significance for the intraindividual variability in G1 (40 ⫾ 25% vs 28 ⫾ 16%; P ⫽ .01).
Table 3. Cyclosporine Dose and Whole Blood Trough Concentration Before and After Conversion to NEO Time After Transplant (y)
SIM
NEO
3.8 4.0 4.3 4.5 4.6 4.7 5.5 6.4 7.4 8.5 9.3
Dose Reduction (%)**
Dose (mg) G1
G2
P*
247 ⫾ 77 248 ⫾ 77 247 ⫾ 77 246 ⫾ 77 240 ⫾ 79 238 ⫾ 79 231 ⫾ 75 226 ⫾ 75 214 ⫾ 72 207 ⫾ 71 183 ⫾ 75
314 ⫾ 98 314 ⫾ 96 315 ⫾ 94 313 ⫾ 96 297 ⫾ 80 293 ⫾ 80 284 ⫾ 76 263 ⫾ 60 259 ⫾ 56 245 ⫾ 51 218 ⫾ 52
⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .004 .001 .004 .131
G1
⬍1 3 4 6 9 13 16 26
Concentration (ng/mL)
Dose-Normalized Concentration (ng/mL)/mg
G2
G1
G2
P*
G1
G2
P*
⬍1 6 7 9 16 17 22 30
125 (55) 132 (50) 153 (69) 192 (61) 178 (54) 185 (38) 170 (55) 179 (40) 148 (64) 138 (47) 121 (50)
171 (61) 187 (54) 203 (50) 214 (51) 198 (49) 189 (48) 181 (48) 185 (55) 155 (43) 156 (41) 121 (50)
.005 .001 .006 .263 .315 .838 .598 .769 .677 .253 .981
0.53 ⫾ 0.38 0.55 ⫾ 0.25 0.62 ⫾ 0.39 0.78 ⫾ 0.47 0.76 ⫾ 0.41 0.81 ⫾ 0.36 0.81 ⫾ 0.54 0.80 ⫾ 0.32 0.71 ⫾ 0.42 0.66 ⫾ 0.30 0.69 ⫾ 0.27
0.57 ⫾ 0.36 0.62 ⫾ 0.34 0.67 ⫾ 0.33 0.72 ⫾ 0.40 0.66 ⫾ 0.32 0.62 ⫾ 0.29 0.67 ⫾ 0.36 0.73 ⫾ 0.46 0.63 ⫾ 0.30 0.68 ⫾ 0.35 0.61 ⫾ 0.36
.648 .240 .489 .404 .169 .039 .154 .515 .301 .820 .646
*Independent sample Student t test (G1 vs G2). %CV are in parenthesis. **Percent-dose reduction related to the last SIM dose before conversion to NEO.
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Fig 2. Cyclosporine total daily doses and whole blood concentrations. Open circles and triangles are single- (G1) and twice(G2) daily doses; solid circles and triangles are C24 (G1) and C12 (G2) cyclosporine trough concentrations, respectively (*P ⬍ .05; G1 vs G2).
Acute Rejection Episodes
DISCUSSION
There were three (3.4%) episodes of acute rejection in G2. They occurred at 93, 160, and 456 days after conversion and were graded as Banff IA, III, and IIA. Two of them were successfully treated with methylprednisolone with full recovery of graft function. The severe rejection occurred in a patient with previously good graft function (creatinine level of 1.6 mg/dL), who was admitted with abrupt oliguria and diffuse thrombosis of small arteries in a biopsy fragment, leading to subsequent graft loss. Noncompliance could not be ruled out. Cyclosporine blood levels at the time of rejection were 150, 77, and 195 ng/mL.
In this transplant population, patients were switched from BID to QD schedule relatively long after transplantation (11.6 ⫾ 16.6 months) due to unsatisfactory graft function. A retrospective analysis confirmed this assumption because, in the majority of these patients, graft function showed a stable improvement after switching from a twice a day to a once a day schedule (2.5 ⫾ 2 vs 1.7 ⫾ 0.5 mg/dL; P ⫽ .010). The fact that a long-term (50.6 ⫾ 27.2 months) and stable improvement could be achieved with this strategy supports the concept described above, suggesting this dose frequency was more appropriate as previously described by Kahan et al31 Compared with patients using a BID schedule, analysis of baseline demographic characteristics showed that patients receiving cyclosporine QD could be described as a high-risk population for developing chronic allograft nephropathy because patients in this group showed longer follow up, higher incidence of delayed graft function among cadaveric recipients, and higher incidence of acute rejection episodes, recognized variables significantly associated with reduced allograft survival. This was confirmed by the significantly higher mean creatinine values in this group at baseline (Table 2). The results of this study demonstrated that conversion from SIM to NEO using a QD schedule is safe and effective in preserving graft function and preventing graft loss compared with the traditional BID schedule, either in short-term or long-term follow-up. The rate of creatinine increment, mean blood pressure, and number of antihypertensive drugs, graft loss, and death were not different comparing QD and BID. Moreover, no acute rejection episodes were observed in QD group.
Patient and Graft Survival
To determine whether the conversion showed any impact on long-term patient and graft survival, we compared the rates of patient death and graft loss. There were no significant differences in either patient or graft survival comparing QD and BID treatment schedules (Fig 3). Five-year patient and graft survival rates after conversion were 76.5% versus 78.2% and 93.3% versus 86.2, respectively. Overall, there were 12 deaths (3 in G1 and 9 in G2) and 14 graft losses (7 in each group). The causes of death included infection (1 in G1 and 5 in G2) and cardiovascular disease (2 in G1 and 3 in G2). Thirteen grafts were lost due to chronic allograft nephropathy (7 in G1 and 6 in G2) and 1 due to refractory severe acute rejection in G2. Ten patients in G1 (19%) and 24 in G2 (27%) had their immunosuppressive regimen changed, either in the frequency of cyclosporine administration or from cyclosporine to another drug. There were 9 lost to follow-up (4 in G1 and 5 in G2).
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Fig 3. Patient and graft survival after conversion to NEO. Open circles and triangles are patient and solid circles and triangles are graft survival in single- (G1) and twice- (G2) daily cyclosporine dose groups, respectively (P ⬎ .05).
In the long-term follow-up, either cyclosporine overdosing or underdosing likely would produce a detrimental effect on graft function in these patients. It has been described that patients with poor or progressive deteriorating allograft function benefit from cyclosporine dose reduction or cyclosporine withdrawal suggesting that, at least in part or in a fraction of these patients, cyclosporine overdosing is involved.37– 42 Moreover, stable kidney transplant patients receiving NEO underwent safe and effective cyclosporine dose reduction upon changing monitoring strategy from trough to C2 concentrations, suggesting that these patients may have been overdosed.43 The maintenance on a QD schedule appeared to have minimized graft toxicity and preserved function because, although showing worse graft function at the time of conversion to NEO, no significant differences were observed comparing the rate of creatinine increment with that seen in the BID group. Moreover, the rate of function loss was slower in the G1 compared to the G2 group. On the other hand, cyclosporine underdosing has been associated with chronic allograft nephropathy.44 – 46 The lack of acute rejection and the similar rate of graft loss due to chronic allograft nephropathy compared to a relatively lower risk population (G2) support the idea that the dosing frequency was effective in preventing acute rejection and allograft loss. The critical issue related to the safety and efficacy of this strategy is the cyclosporine concentration in each group. First, G2 patients showed typical C12 whole blood cyclosporine trough concentrations, receiving either SIM or NEO (Table 3; Fig 2). While on SIM, G1 patients showed worse graft function but significantly lower cyclosporine C24 concentrations, making a direct comparison between the
two groups difficult to interpret. Bunke et al showed an improvement in glomerular filtration rate in cardiac transplant recipients switched from BID to QD schedule.47 The criticism was that the benefit observed was due to reduction in drug absorption and reduced trough concentrations.48 Johnston and Holt stated that to compare the renal function of patients on QD and BID dosing schedules the patients should have been dosed to the same trough cyclosporine concentration.48 Although our transplant population was dosed to and benefited from a lower trough concentration for 50 months while on single daily doses of SIM, after conversion to NEO there were no differences between QD and BID, validating a direct comparison of the effect of the two treatment schedules on long-term graft function. After conversion, patients in G1 showed an increase in cyclosporine concentration, probably due to increased absorption, reaching similar concentrations to that seen in G2 group, although still receiving significantly lower cyclosporine doses. This behavior can be explained by better improvement in absorption in G1 compared to G2, because after the conversion to NEO dose-normalized cyclosporine concentration showed a higher increase in G1 compared to G2 (Table 3). Schadeli et al observed similar findings analyzing steady-state pharmacokinetics or once-daily cyclosporine in 60 stable renal transplant recipients before and after conversion from SIM to NEO. This group suggested that, after the administration of higher single daily doses, the rapid formation of readily absorbable microemulsion results in rapid absorption and a short residence time in a small “absorption time window” in the gut, reducing exposure to gut first-pass metabolism and result-
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ing in better dose linearity49,50 It also was suggested that QD would result in a higher peak and peak/trough concentration ratio leading to toxic effect.48 Although we have not measured peak concentrations systematically, there is no reason to predict that they were not higher in QD versus BID. Taking into consideration baseline demographics, we would anticipate that these patients showing higher cyclosporine concentration after conversion to NEO would be at risk for nephrotoxicity after a 1:1 conversion ratio.29 Nonetheless, no detrimental effect was observed during a 5-year follow-up under similar cyclosporine dose reductions and cyclosporine C24 and C12 trough concentrations, and, in fact, a slower rate of function graft loss was observed in the QD group (Fig 1). Two main reasons may be involved in this result. First, patients in G1 may have benefited from higher peak concentrations, currently associated with better outcomes51 and may have been protected from nephrotoxicity because a QD schedule allows “drug holiday”31,32 which may be associated with a lower frequency of daily cyclosporineinduced hypoperfusion52 and superior systemic and hemodynamic profiles.53 Another possibility is the reduced intrapatient variability observed in G1 after conversion to NEO, which has been associated with superior long-term graft survival.23 The pattern of cyclosporine concentration changes of this study is supported by a recent detailed pharmacokinetic study in patients receiving single daily doses of cyclosporine switched to NEO.50 The rate of changes in immunosuppression cannot be implicated in these findings because higher percentage of changes were seen in G2, mainly due to conversion from a BID to a QD NEO schedule. Maximal inhibition of calcineurin correlates directly with peak cyclosporine blood concentrations and with efficacy in retrospective and prospective clinical trials.54 Neither the extent nor the duration of inhibition required to produce immunosuppression, however, have been directly assessed. Moreover, it has not been determined yet whether two daily cycles of calcineurin inhibition, diurnal and nocturnal, are required to produce adequate immunosuppression either in short-term or long-term follow-up because NEO is prescribed twice daily due to pharmacokinetic and not to pharmacodynamic reasons. If two peak concentrations were required to produce adequate immunosuppression, it would be advisable to monitor the nocturnal C2 because circadian variation, timing of prednisone dose and meals,22 and drug coadministration, such as sirolimus,55 have been described to be associated with significantly reduced nocturnal peak concentrations. Although long-term graft survival has been achieved with QD SIM56,57 this study is the first to demonstrate that this strategy also may be used with NEO. Whether single daily doses of NEO can produce comparable or superior therapeutic efficacy/toxicity profile compared to the traditional BID schedule when used early after transplantation is not known yet but unquestionably this issue deserves further
SAMPAIO, PARK, FELIPE ET AL
investigations due to significant improvements in compliance, safety, and cost savings this strategy may produce. REFERENCES 1. Klintmalm GB, Iwatsuki S, Starzl TE: Transplantation 32:488, 1981 2. Ferguson RM, Rynasiewicz JJ, Sutherland DER, et al: Surgery 92:175, 1982 3. no-listed. Lancet 986, 1983 4. The Canadian Multicentre Transplant Group: N Engl J Med 314:1219, 1986 5. Ponticelli C, Minetti L, Di Palo FQ, et al: Transplantation 45:908, 1988 6. Wrenshall LE, Matas AJ, Canafax DM, et al: Transplantation 50:233, 1990 7. Kahan BD, Wideman CA, Reid M, et al: Transplant Proc 16:1195, 1984 8. Kahan BD: Transplantation 40:457, 1985 9. Lindholm A, Kahan BD: Clin Pharmacol Ther 54:205, 1993 10. Savoldi S, Sandrini S, Scolari F, et al: Transpl Proc 19:1720, 1987 11. Hiesse C, Prevost P, Busson M, et al: Transpl Int 1:149, 1988 12. Tarantino A, Aroldi A, Stucchi L, et al: Transplantation 52:52, 1991 13. Hsieh H, Chen CH, Lai MK: Transplant Proc 26:1922, 1994 14. Ptachcinski RJ, Venkataramanan R, Rosenthal JT, et al: Clin Pharmacol Ther 38:296, 1985 15. Ohlman S, Lindholm A, Hagglund H, et al: Eur J Clin Pharmacol 44:265, 1993 16. Kahan BD: Transplant Proc 17(suppl 1):303, 1985 17. Mueller EA, Kovarik JM, van Bree JB, et al: Transplantation 57:1178, 1994 18. Wahlberg J, Wilczek HE, Fauchald P, et al: Transplantation 60:648, 1995 19. Keown P, Landsberg D, Halloran P, et al: Transplantation 62:1744, 1996 20. Chapman JR, O’Connell PJ, Bovington KJ, et al: Transplantation 61:1699, 1996 21. Feutren G, Wong R, Jin J, et al: Transplant Proc 28:2177, 1996 22. Kahan BD, Dunn J, Fitts C, et al: Transplantation 59:505, 1995 23. Kahan BD, Welsh M, Schoenberg L, et al: Transplantation 62:599, 1996 24. Mendez R, Abboud H, Burdick J, et al: Clin Ther 21:160, 1999 25. Kovarik JM, Mueller EA, van Bree JB, et al: Ther Drug Monit 16:232, 1994 26. Mueller EA, Kovarik JM, van Bree JB, et al: Transplantation 57:1178, 1994 27. Neumayer HH, Budde K, Farber L, et al: Clin Nephrol 45:326, 1996 28. Pescovitz MD, Barone G, Choc MG Jr, et al: Transplantation 63:778, 1997 29. Curtis JJ, Lynn M, Jones PA: J Am Soc Nephrol 9:1293, 1998 30. Brennan DC, Barbeito R, Burke J, et al: Kidney Int 56:685, 1999 31. Kahan BD, Grevel J: Transplantation 46:631, 1988 32. Vathsala A, Lee WT, Lu YM, et al: Transplant Proc 30:1746, 1998 33. Arvind C, Vathsala A, Woo KT: Transplant Proc 32:1681, 2000 34. Cole E, Keown P, Landsberg D, et al: Transplantation 65:505, 1998 35. Neumayer HH, Budde K, Farber L, et al: Clin Nephrol 45:326, 1996 36. Sijpkens YW, Mallat MJ, Siegert CE, et al: Clin Nephrol 55:1491, 2001
CONVERSION FROM SANDIMMUN TO NEORAL 37. Bennett WM, DeMattos A, Meyer MM, et al: Kidney Int 50:1089, 1996 38. Weir MR, Anderson L, Fink JC, et al: Transplantation 64:1706, 1997 39. Mourad G, Vela C, Ribstein J, et al: Transplantation 65:661, 1998 40. Franceschini N, Alpers CE, Bennett WM, et al: Am J Kidney Dis 32:2478, 1998 41. de Mattos AM, Olyaei AJ, Bennett WM: Am J Kidney Dis 35:333, 2000 42. Weir MR, Ward MT, Blahut SA, et al: Kidney Int 59:1567, 2001 43. Cole E, Maham N, O’Grady C, et al: Am J Transpl 2(suppl 3):379, 2002 44. Almond PS, Matas A, Gillingham K, et al: Transplantation 55:752, 1993 45. Citterio F, Torricelli P, Serino F, et al: Transplant Proc 30:1688, 1998 46. Opelz G, Dohler B: Transplantation 72:1267, 2001 47. Bunke M, Sloan R, Brier M, et al: Transplantation 59:537, 1995
3161 48. Johnston A, Holt DW: Transplantation 60:1376, 1995 49. Mueller EA, Kovarik JM, van Bree JB, et al: Pharm Res 11:301, 1994 50. Schadeli F, Marti HP, Frey FJ, et al: Clin Pharmacokinet 41:59, 2002 51. Group CNRTS: Transplantation 72:1024, 2001 52. Perico N, Ruggenenti P, Gaspari F, et al: Transplantation 54:56, 1992 53. De Mattos AM, Norman DJ, Olyaei A, et al: Presented at the 31st Annual Meeting of the American Society of Nephrology, Philadelphia, PA, USA, 1998 (Abstract A3425) 54. Halloran PF, Helms LMH, Kung L, et al: Transplantation 68:1356, 1999 55. Kaplan B, Meier-Kriesche HU, Napoli KL, et al: Clin Pharmacol Ther 63:48, 1998 56. Montagnino G, Tarantino A, Maccario M, et al: Am J Kidney Dis 35:1135, 2000 57. Tarantino A, Montagnino G, Cesana B, et al: Transplant Proc 33:3409, 2001
S
ANDIMMUN (SIM), the oil-based cyclosporine formulation, has been used to prevent acute rejection after kidney transplantation for more than 20 years. In the first clinical trials cyclosporine was administered as single daily doses and adjustments were performed according to rigid and predetermined algorithms, on occurrence of side effects, or to assure long-term compliance.1– 6 The introduction of therapeutic drug monitoring offered a better strategy to improve the therapeutic use of cyclosporine.7–9 Kahan et al proposed that dosing frequency should be predicted by determining drug elimination rates in the context of full pharmacokinetic studies and suggested that cyclosporine should be dosed every two half-lives due to its narrow therapeutic index and the relationship between trough levels and toxic complications.8 Savoldi et al, however, demonstrated that with significantly lower doses the administration of cyclosporine twice daily produced similar trough concentrations and efficacy outcomes although higher incidence of hepatotoxicities and nefrotoxicities were observed during the first month.10 The so-called triple therapy consisted of cyclosporine, azathioprine, and prednisone, which gained wide acceptance among transplantation centers, consisted of using lower cyclosporine doses administered twice daily.11,12 Wrenshall et al described an increase in the incidence of late acute rejection after switching patients from BID to QD schedules 1 year after transplantation. In this study, however, whole blood concentrations in those patients were less than 50 ng/mL.6 Hsieh et al successfully switched 17 patients who had relatively high cyclosporine trough concentrations while on a BID schedule after 1 year of transplantation.13 Difficulties in establishing dosing frequency for the oil-based cyclosporine formulation is related to its considerable interindividual and intraindividual pharmacokinetic variability after transplantation, mainly due to differences in the rate and extent of its absorption.8,14,15 Therefore, it is not surprising that many patients benefited from individualized dosing schedules, especially those with cyclosporine-associated toxic effects.8,16 The new microemulsion formulation of cyclosporine (NEO) improved the absorption characteristics of cyclosporine. Not only the extent of absorption improved, mainly in the previous poor absorbers, but also the rate so that
peak concentrations are consistently achieved earlier after drug administration.17–21 Moreover, interpatient and intrapatient variability was reduced, facilitating therapeutic drug monitoring and perhaps improving long-term graft survival due to significantly less fluctuation in cyclosporine blood concentration.22–24 NEO was developed to be given in a twice a day schedule, supported by its more predictable and less variable pharmacokinetics.25,26 Based on the pharmacokinetic advantages of NEO, many studies addressed the efficacy and safety of the conversion from SIM to NEO. First, well-designed conversion trials demonstrated that the 1:1 conversion ratio was safe as long as therapeutic drug monitoring was implemented to correct for significant improvement in cyclosporine absorption, preventing the emergence of toxic side effects.27–30 There were no established guidelines, however, to convert those patients on single daily doses of SIM. Vasala et al, in a transplant population with stable and excellent graft function (creatinine ⫽ 124 ⫾ 27 mol/L), reported a parallel increase in serum creatinine and cyclosporine exposures, measured either by trough or average cyclosporine concentrations, in 55.6% of the patients converted from once a day SIM to twice-daily NEO. They suggested that the lack of drug holiday (decrease of cyclosporine concentrations over a 24-hour dosing interval31) after conversion to twice-daily NEO could have been involved and that conversion to once daily NEO could have prevented this effect.32 Later, the same group conducted a conversion study from SIM to NEO in 24 stable kidney transplant patients with underlying liver disease receiving single daily doses of cyclosporine. Significant increases in cyclosporine blood concentrations were observed and dose reductions were necessary to avert nephrotoxicity during a 4-week follow-up.33 In the patient cohort presented here, the most frequent cause to switch from twice-daily to single-daily SIM dosing was unsatisfactory graft function with clinical and/or histoFrom the Nephrology Division, Hospital do Rim e Hipertensa˜o, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil. Address reprint requests to Helio Tedesco Silva, Jr, MD, Nephrology Division, Hospital do Rim e Hipertensa˜o, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, Brazil 04038-002. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03659-X
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logical signs of cyclosporine toxicity. Therefore, our major concern was that the conversion of these patients from once a day SIM to a twice-daily NEO regimen would increase their cyclosporine exposure and would likely compromise graft function.29,34 Furthermore, studies also have shown that conversion should be very cautious in patients with graft dysfunction, in which a 1:1 direct conversion could lead to worsening of graft function.29,35,36 We present here the short-term and long-term impacts of the conversion from once-daily SIM to once-daily NEO on graft function, and on graft and patient survival, as well as detailed analysis of cyclosporine dose and whole blood concentrations measured during a 6-year follow-up period. METHODS Population Between October 9, 1995 and November 13, 1997, 182 kidney transplant recipients receiving cyclosporine-based immunosuppressive therapy were converted from SIM to NEO at our institution. All patients were receiving cyclosporine-based immunosuppressive therapy since the first day after the transplantation. At the time of conversion, 119 (65.4%) patients were receiving cyclosporine, azathioprine, and prednisone; 36 (19.8%) were receiving cyclosporine and Prednisone; 17 (9.3%) were receiving cyclosporine and azathioprine; and 10 (5.5%) were receiving cyclosporine alone. Eighty-two patients (45%) were receiving SIM in a once-daily schedule (QD) and 100 (55%) in a twice-daily (BID) schedule at the time of conversion. This was a retrospective comparative study of two treatment schedules after the conversion from SIM to NEO in stable kidney transplanted patients.
Conversion Protocol The decision to switch from SIM to NEO was left at the discretion of the patients own physicians. All patients were informed of the risks and benefits before the conversion. Minimum eligibility criteria were stable kidney allograft function and lack of clinical or biopsy-confirmed acute rejection within the last 3 months. Eligible patients were switched from SIM to NEO using a 1:1 ratio. Cyclosporine blood concentrations were monitored after conversion and adjustments were made for safety and tolerability. For the purpose of this retrospective analysis, we only included patients who met the following criteria: (1) patients who were receiving the same SIM schedule (BID or QD) in the last 3 visits prior to conversion; (2) patients who were converted to NEO following the same SIM treatment schedule (BID 3 BID; QD 3 QD); and (3) patients who were kept in the same NEO schedule for at least 1 year of follow-up. Therefore, for this analysis we selected 141 patients, 53 on a QD (group 1, G1) and 88 on a BID SIM schedule (group 2, G2). The majority of patients excluded from G1 were converted from QD to BID cyclosporine schedule.
Follow-Up Parameters Because patients had a wide range of posttransplantation follow-up time, mean times of the three pre-conversion run-in visits and four post-conversion follow-up visits during the first year were ⫺ 0.7 ⫾ 0.4, ⫺ 0.4 ⫾ 0.2, and ⫺ 0.2 ⫾ 0.1, and 0.1 ⫾ 0.05, 0.2 ⫾ 0.01, 0.4 ⫾ 0.1, and 1 ⫾ 0.2 years, respectively. Thereafter, follow-up parameters were obtained every year up to 5 years after the conversion. There were no significant differences comparing mean
SAMPAIO, PARK, FELIPE ET AL visit times of G1 versus G2 (not shown). At each visit weight, blood pressure, number of antihypertensive drugs, dose of azathioprine and prednisone, dose and blood concentrations of cyclosporine, and creatinine plasma levels were obtained. Because patients had stable but a relatively wide range of graft function (creatinine levels from 0.7 to 3.5 mg/dL at first pre-conversion visit) and to analyze whether the conversion produced a deterioration of graft function, either in a QD or BID schedule, for each patient graft function also was analyzed using the 1/creatinine versus time strategy. For this purpose, all creatinine values between the first and the last study visit were included (at least seven time points were used for each patient). The slopes of the regression lines were compared between the two groups. Cyclosporine blood concentrations were measured before the morning drug administration, 24 (C24) and 12 (C12) hours after the last dose in groups G1 and G2, respectively. Inter-individual and intraindividual variability was expressed as percent coefficient of variation (%CV ⫽ standard deviation/mean). Cyclosporine whole blood concentrations were determined with monoclonal antibody using the fluorescence polarization immunoassay kit (Abbott Laboratories, Chicago, Ill, USA), according to the manufacture’s directions. Performance was assessed on the basis of a three-point quality control concentration range of low (70 ng/mL), intermediate (300 ng/mL), and high (600 ng/mL) concentrations, and the limit of quantification of the assay was 25 ng/mL.
Graft Dysfunction Due to the large period of observation, from October 9, 1995 to March 31, 2002, it was difficult to establish uniform criteria for acute rejection. Therefore, in this retrospective analysis, preconversion acute rejection episodes were defined as a graft dysfunction, which responded to a full treatment with steroids or were biopsy-confirmed. After conversion, graft dysfunction was defined as a 20% or more increase in creatinine values compared to the last value before conversion. Patients with graft dysfunction were followed closely with repeated measurements of serum creatinine levels, cyclosporine blood levels, and ultrasound evaluations. If cyclosporine blood level was equal or higher than the last value before conversion, cyclosporine dose was decreased until a comparable or a lower blood level was observed. At the discretion of the physician a core graft biopsy was performed based on his or her clinical judgment. If no features of acute rejection were observed, then a further reduction of cyclosporine dose was done in an attempt to bring the creatinine level back to the previous value before conversion. In case of biopsy-proven acute rejection, a full course of methylprednisolone was administered. Another biopsy was performed if no or partial response to steroid therapy was observed.
Patient and Graft Survival All patients were included in the analysis so as to assess patient and graft survival in each entire group. Graft survival was determined noting grafts losses and patient deaths. Patients who were lost to follow-up, had a change in either treatment schedules (from BID to QD or vice versa), or who were withdrawn from cyclosporine were not included in the analysis.
Statistical Analysis Demographic characteristics were analyzed by two-sided unpaired Student t tests (continuous variables) and by chi-square tests (categorical variables). Summary statistics were expressed as mean and standard deviation, or frequencies or median and range,
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Table 1. Demographic Characteristics*
N Age (y)** Weight (kg)** Gender, N (%) Male Female Ethnicity, N (%) White Mulatto Black Others Cause of endostage renal disease, N (%) Chronic glomerulonephritis Hypertension Diabetes melitus Polycistic kidney disease Unknown origin Others Donor source**, N (%) Living donor Cadaver donor Retransplantation, N (%) Cold ischemic time (h)
Delayed graft function**, N (%) Acute rejection**, N (%) Living donor Cadaver donor Imunnosupression, N (%) Cyclosporine, azathioprine, and prednisone Cyclosporine and azathioprine Cyclosporine and prednisone CSA Cyclosporine Conversion (mo)**
Total
Group 1
Group 2
141 31.9 ⫾ 13.7 (5.0 – 62.0) 61.1 ⫾ 15.6 (19.4 –101.8)
53 36.9 ⫾ 10.8 (17.0 – 62.0) 64.9 ⫾ 11.5 (47.0 –96.7)
88 29.0 ⫾ 14.4 (5.0 –58.0) 58.8 ⫾ 17.3 (19.4 –101.8)
81 (57.4) 60 (42.6)
36 (67.9) 17 (32.1)
45 (51.1) 43 (48.9)
83 (58.9) 41 (29.1) 11 (7.8) 6 (4.2)
29 (54.7) 16 (30.2) 5 (9.4) 3 (5.7)
54 (61.4) 25 (28.4) 6 (6.8) 3 (3.4)
70 (49.6) 7 (5.0) 4 (2.8) 4 (2.8) 27 (19.2) 29 (20.6)
26 (49.1) 5 (9.4) 1 (1.9) 2 (3.8) 12 (22.6) 7 (13.2)
44 (50.0) 2 (2.3) 3 (3.4) 2 (2.3) 15 (17.0) 22 (25.0)
47 (33.3) 94 (66.7) 2 (1.4) 26.5 ⫾ 8.1 (5.0 – 47.0) N ⫽ 91 34 (37.4) 83 (58.9) 22 (46.8) 61 (64.9)
26 (49.1) 27 (50.9) 2 (3.8) 24.7 ⫾ 9.0 (12.0 – 47.0) N ⫽ 26 15 (57.7) 38 (71.7) 16 (30.2) 22 (41.5)
21 (23.9) 67 (76.1) 0 (0.0) 27.2 ⫾ 8.1 (5.0 – 43.0) N ⫽ 65 19 (29.2) 45 (51.1) 6 (6.8) 39 (44.3)
97 (68.8)
37 (69.8)
60 (68.2)
11 (7.8) 26 (18.4) 7 (5.0) 51.3 ⫾ 26.3 (6 –134)
4 (7.5) 10 (18.9) 2 (3.8) 59.7 ⫾ 23.3 (17–133)
7 (8.0) 16 (18.1) 5 (5.7) 46.3 ⫾ 26.8 (6 –134)
*Mean ⫾ standard deviation, (range); **P ⬍ .05 G1 vs G2.
respectively. General linear model (GLM) for repeated measures was used to compare weight, blood pressure, number of antihypertensive drugs, dose of azathioprine and prednisone, and creatinine plasma levels, with visit and group used as sources of variation before and after conversion. Least squares linear regressions were used to calculate the evolution of 1/creatinine versus time, and the slopes obtained from each patient of G1 and G2 groups were compared using a two-sided unpaired Student t test. Patient and graft survival were calculated using the Kaplan-Meier method and differences between the two groups were identified using the log-rank test. Statistical analysis was done using SPSS 7.5 software (SPSS Inc.). Differences were considered significant at P ⬍ .05.
RESULTS Demographic Characteristics
The demographic characteristics are shown in Table 1. Mean age was 31.9 ⫾ 13.7 years and mean weight was 61.1
⫾ 15.6 kg. Of the total 57.4% were men and 58.9% were white. The majority of the patients (98.6%) were recipients of first kidney transplants. Recipients of cadaveric allografts (66.7%) had a mean cold ischemia time of 26.5 ⫾ 8.1 hours and 37.4% of them developed delayed graft function. Acute rejection rate was 58.9%, being 46.8% in living and 64.9% in cadaveric allograft recipients, respectively. At the time of conversion, 68.8% of the patients were receiving cyclosporine, azathioprine, and prednisone, 18.4% were receiving cyclosporine and prednisone, 7.8% were receiving cyclosporine and azathioprine, and 5% were receiving cyclosporine alone. Compared to G2, G1 showed older (36.9 ⫾ 10.8 vs 29 ⫾ 14.4 years; P ⫽ .001) and heavier (65 ⫾ 11.7 vs 58.5 ⫾ 16.8; P ⫽ .022) patients, higher proportion of living allograft recipients (49.1% vs 23.9%; P ⫽ .003), higher incidence of delayed graft function (57.7% vs 29.2%; P ⫽
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SAMPAIO, PARK, FELIPE ET AL Table 2. Graft Function and Blood Pressure Control Before and After Conversion From SIM to NEO Follow-Up Time After
SIM
NEO
Systolic Blood Pressure (mm Hg)
Creatinine (mg/dL)
Conversion (y)
Transplantation (y)
⫺0.7 ⫺0.4 ⫺0.2 0.1 0.2 0.4 1.0 2.0 3.0 4.0 5.0
3.8 4.0 4.3 4.5 4.6 4.7 5.5 6.4 7.4 8.5 9.3
GLM** ⫺0.7 3 1.0
1.0 3 5.0
G1
G2
1.7 ⫾ 0.5 1.5 ⫾ 0.5 1.8 ⫾ 0.5 1.4 ⫾ 0.5 1.7 ⫾ 0.4 1.4 ⫾ 0.5 1.8 ⫾ 0.6 1.6 ⫾ 0.5 1.8 ⫾ 0.6 1.6 ⫾ 0.7 1.9 ⫾ 0.7 1.7 ⫾ 0.5 2.0 ⫾ 0.8 1.6 ⫾ 0.6 1.8 ⫾ 0.6 1.5 ⫾ 0.5 2.1 ⫾ 1.4 1.7 ⫾ 0.6 2.0 ⫾ 1.0 1.6 ⫾ 0.5 2.1 ⫾ 0.6 1.8 ⫾ 0.4 Within visits Between groups Within visits ⫻ groups Within visits Between groups Within visits ⫻ groups
Dyastolic Blood Pressure (mm Hg)
No. of Antihypertensive Drugs
P*
G1
G2
P*
G1
G2
P*
G1
G2
P*
.007 ⬍.001 .001 .011 .043 .027 .004 .024 .023 .005 .075 ⬍.001 .001 .566 ⬍.001 .236 .131
136 ⫾ 16 135 ⫾ 18 132 ⫾ 13 133 ⫾ 14 135 ⫾ 18 137 ⫾ 21 135 ⫾ 19 140 ⫾ 19 142 ⫾ 23 135 ⫾ 21 145 ⫾ 14
128 ⫾ 19 127 ⫾ 19 127 ⫾ 19 127 ⫾ 22 127 ⫾ 24 126 ⫾ 21 128 ⫾ 23 132 ⫾ 23 135 ⫾ 18 139 ⫾ 19 133 ⫾ 19
.013 .017 .067 .087 .028 .006 .069 .069 .070 .467 .075 .777 .006 .917 .474 .249 .609
88 ⫾ 9 89 ⫾ 14 87 ⫾ 12 85 ⫾ 11 86 ⫾ 12 89 ⫾ 20 88 ⫾ 12 90 ⫾ 13 88 ⫾ 11 85 ⫾ 13 92 ⫾ 11
86 ⫾ 13 84 ⫾ 14 82 ⫾ 15 83 ⫾ 15 83 ⫾ 16 82 ⫾ 14 82 ⫾ 16 85 ⫾ 16 85 ⫾ 12 86 ⫾ 12 84 ⫾ 9
.407 .028 .032 .304 .317 .020 .021 .049 .143 .522 .044 .023 .022 .523 .399 .142 .680
1.4 ⫾ 1.0 1.5 ⫾ 1.0 1.5 ⫾ 1.0 1.5 ⫾ 1.0 1.4 ⫾ 1.0 1.4 ⫾ 1.0 1.4 ⫾ 1.1 1.4 ⫾ 1.0 1.4 ⫾ 1.2 1.4 ⫾ 1.1 1.4 ⫾ 1.3
1.2 ⫾ 1.0 1.2 ⫾ 1.0 1.2 ⫾ 1.1 1.2 ⫾ 1.1 1.4 ⫾ 1.5 1.3 ⫾ 1.1 1.2 ⫾ 1.1 1.2 ⫾ 1.1 1.3 ⫾ 1.1 1.4 ⫾ 1.2 1.6 ⫾ 1.1
.282 .157 .080 .129 .804 .782 .276 .523 .520 .879 .759 .706 .273 .087 .002 .330 .278
*Independent sample Student t test (G1 vs G2). **General Linear Model for repeated measures (G1 vs G2).
.016), higher incidence of acute rejection (71.7% vs 51.1%; P ⫽ .025), and longer posttransplantation follow-up at the time of conversion (59.7 ⫾ 23.3 vs 46.3 ⫾ 26.8; P ⫽ .003). Patients in G1 were switched from BID to QD SIM schedule 11.6 ⫾ 16.6 months (0.3 to 80.2 months) after transplantation when mean creatinine values were 2.46 ⫾ 2 mg/dL (1.2 to 13 mg/dL). Therefore, at the time of conversion to NEO, patients were receiving QD SIM for a mean time of 50.6 ⫾ 27.2 months (range: 6 to 134 months). Follow-Up Parameters
During pre-conversion baseline visits up to 1 year after conversion to NEO, mean creatinine values increased in both groups (1.7 ⫾ 0.5 vs 2.0 ⫾ 0.8 mg/dL, G1; 1.4 ⫾ 0.5 vs 1.6 ⫾ 0.6 mg/dL, G2, within visits; P ⬍ .001, GLM for repeated measures, Table 2). Patients in G1 still showed higher mean creatinine values in all study visits compared to G2 (between groups; P ⫽ .001). Finally, patients in G1 showed similar a increment in creatinine values compared to patients in G2 (within visit group; P ⫽ .566). Blood pressure also was significantly higher among patients in G1 at any visit during the first year after conversion to NEO with no significant differences in the mean number of antihypertensive drugs. Overall, this data demonstrated that conversion from SIM to NEO was safe in a short-term follow-up, and that no significant differences in graft function or blood pressure control were found comparing patients on QD or BID NEO schedules. Extending the analysis from 1 to 5 years after conversion to NEO, the results were still very similar. There was a persistent and similar rate of increment in mean creatinine
values in both groups (2.0 ⫾ 0.8 vs 2.1 ⫾ 0.6 mg/dL, G1; 1.6 ⫾ 0.6 vs 1.8 ⫾ 0.4 mg/dL, G2, within visits; P ⬍ .001; between groups, P ⫽ .236; within visit group, P ⫽ .131), with no significant differences in blood pressure. The mean number of anti-hypertensive drugs used in G2 between 1 and 5 years after conversion increased significantly, however, from 1.2 ⫾ 1.1 vs 1.6 ⫾ 1.1 mg/dL (P ⫽ .002). Therefore, even after a long-term follow-up period, conversion from SIM to NEO was safe with no significant differences in graft function and blood pressure control comparing patients receiving QD or BID NEO schedules (Table 2). To confirm short-term and long-term safety and further determine whether the conversion from SIM to NEO in these two treatment schedules showed any differential detrimental effects on long-term graft function, the decrease in allograft function was compared by analyzing the slopes of the plots of 1/creatinine as a function of time elapsed after the first study visit in each group. Patients in G1 showed a slower rate of decline in graft function comparing mean slopes of each group during a 5-year follow-up (⫺0.00008 ⫾ 0.000015 vs ⫺0.00015 ⫾ 0.00020 [mg/dL]⫺1 per day; 95% confidence interval ⫽ 0.0000067 ⫺ 0.0001347; P ⫽ .031; Fig 1). The percentage of patients with worsening graft function, determined by a negative slope, was higher in G2 compared to G1 (87.5% vs 77%; P ⫽ .091). Immunosuppression
There were no statistically significant differences comparing mean values of azathioprine or prednisone doses during the follow-up period while patients were receiving SIM or NEO (data not shown). Mean cyclosporine doses were signifi-
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Fig 1. Slopes showing progression of allograft dysfunction over time using the least squares mean analysis (P ⫽ .031; G1 vs G2).
cantly higher in G2 compared to G1 up to 4 years of follow-up (Table 3). Compared to the first dose of NEO, doses of cyclosporine were equally reduced in both groups during the 5-year follow-up period (G1: 6, 8, 13, 16, and 26%; G2: 9, 16, 17, 22, and 30%). C24 concentrations in G1 were significantly lower compared to C12 concentrations in G2 only during the first 3 study visits, however, when patients were receiving SIM. After conversion to NEO, even receiving lower doses of cyclosporine, C24 levels in G1 were not different compared to C12 levels in G2 (Table 3; Fig 2). Dose-normalized cyclosporine concentrations were not different while patients were receiving SIM but were numerically higher in G1 compared to G2 in most of the visits after conversion to NEO (Table 3). Compared to SIM, percentage increases in dose-normalized cyclosporine
concentrations after conversion to NEO varied from 20% to 43% in G1 compared to ⫺7% to 18% in G2. While patients were receiving SIM, there were no significant differences comparing mean interindividual (G1: 59 ⫾ 13%; G2: 56 ⫾ 7%; P ⫽ .67) and intraindividual (G1: 40 ⫾ 25%; G2: 34 ⫾ 21%; P ⫽ .11) variability in dose⫽normalized cyclosporine blood concentrations, respectively. Similar results were obtained comparing mean interindividual (G1: 51 ⫾ 11%; G2: 53 ⫾ 6%; P ⫽ .69) and intraindividual (G1: 28 ⫾ 16%; G2: 32 ⫾ 20%; P ⫽ .23) variability after conversion to NEO. Decreases in interindividual and intraindividual variability were observed after conversion from SIM to NEO, reaching statistical significance for the intraindividual variability in G1 (40 ⫾ 25% vs 28 ⫾ 16%; P ⫽ .01).
Table 3. Cyclosporine Dose and Whole Blood Trough Concentration Before and After Conversion to NEO Time After Transplant (y)
SIM
NEO
3.8 4.0 4.3 4.5 4.6 4.7 5.5 6.4 7.4 8.5 9.3
Dose Reduction (%)**
Dose (mg) G1
G2
P*
247 ⫾ 77 248 ⫾ 77 247 ⫾ 77 246 ⫾ 77 240 ⫾ 79 238 ⫾ 79 231 ⫾ 75 226 ⫾ 75 214 ⫾ 72 207 ⫾ 71 183 ⫾ 75
314 ⫾ 98 314 ⫾ 96 315 ⫾ 94 313 ⫾ 96 297 ⫾ 80 293 ⫾ 80 284 ⫾ 76 263 ⫾ 60 259 ⫾ 56 245 ⫾ 51 218 ⫾ 52
⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001 .004 .001 .004 .131
G1
⬍1 3 4 6 9 13 16 26
Concentration (ng/mL)
Dose-Normalized Concentration (ng/mL)/mg
G2
G1
G2
P*
G1
G2
P*
⬍1 6 7 9 16 17 22 30
125 (55) 132 (50) 153 (69) 192 (61) 178 (54) 185 (38) 170 (55) 179 (40) 148 (64) 138 (47) 121 (50)
171 (61) 187 (54) 203 (50) 214 (51) 198 (49) 189 (48) 181 (48) 185 (55) 155 (43) 156 (41) 121 (50)
.005 .001 .006 .263 .315 .838 .598 .769 .677 .253 .981
0.53 ⫾ 0.38 0.55 ⫾ 0.25 0.62 ⫾ 0.39 0.78 ⫾ 0.47 0.76 ⫾ 0.41 0.81 ⫾ 0.36 0.81 ⫾ 0.54 0.80 ⫾ 0.32 0.71 ⫾ 0.42 0.66 ⫾ 0.30 0.69 ⫾ 0.27
0.57 ⫾ 0.36 0.62 ⫾ 0.34 0.67 ⫾ 0.33 0.72 ⫾ 0.40 0.66 ⫾ 0.32 0.62 ⫾ 0.29 0.67 ⫾ 0.36 0.73 ⫾ 0.46 0.63 ⫾ 0.30 0.68 ⫾ 0.35 0.61 ⫾ 0.36
.648 .240 .489 .404 .169 .039 .154 .515 .301 .820 .646
*Independent sample Student t test (G1 vs G2). %CV are in parenthesis. **Percent-dose reduction related to the last SIM dose before conversion to NEO.
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Fig 2. Cyclosporine total daily doses and whole blood concentrations. Open circles and triangles are single- (G1) and twice(G2) daily doses; solid circles and triangles are C24 (G1) and C12 (G2) cyclosporine trough concentrations, respectively (*P ⬍ .05; G1 vs G2).
Acute Rejection Episodes
DISCUSSION
There were three (3.4%) episodes of acute rejection in G2. They occurred at 93, 160, and 456 days after conversion and were graded as Banff IA, III, and IIA. Two of them were successfully treated with methylprednisolone with full recovery of graft function. The severe rejection occurred in a patient with previously good graft function (creatinine level of 1.6 mg/dL), who was admitted with abrupt oliguria and diffuse thrombosis of small arteries in a biopsy fragment, leading to subsequent graft loss. Noncompliance could not be ruled out. Cyclosporine blood levels at the time of rejection were 150, 77, and 195 ng/mL.
In this transplant population, patients were switched from BID to QD schedule relatively long after transplantation (11.6 ⫾ 16.6 months) due to unsatisfactory graft function. A retrospective analysis confirmed this assumption because, in the majority of these patients, graft function showed a stable improvement after switching from a twice a day to a once a day schedule (2.5 ⫾ 2 vs 1.7 ⫾ 0.5 mg/dL; P ⫽ .010). The fact that a long-term (50.6 ⫾ 27.2 months) and stable improvement could be achieved with this strategy supports the concept described above, suggesting this dose frequency was more appropriate as previously described by Kahan et al31 Compared with patients using a BID schedule, analysis of baseline demographic characteristics showed that patients receiving cyclosporine QD could be described as a high-risk population for developing chronic allograft nephropathy because patients in this group showed longer follow up, higher incidence of delayed graft function among cadaveric recipients, and higher incidence of acute rejection episodes, recognized variables significantly associated with reduced allograft survival. This was confirmed by the significantly higher mean creatinine values in this group at baseline (Table 2). The results of this study demonstrated that conversion from SIM to NEO using a QD schedule is safe and effective in preserving graft function and preventing graft loss compared with the traditional BID schedule, either in short-term or long-term follow-up. The rate of creatinine increment, mean blood pressure, and number of antihypertensive drugs, graft loss, and death were not different comparing QD and BID. Moreover, no acute rejection episodes were observed in QD group.
Patient and Graft Survival
To determine whether the conversion showed any impact on long-term patient and graft survival, we compared the rates of patient death and graft loss. There were no significant differences in either patient or graft survival comparing QD and BID treatment schedules (Fig 3). Five-year patient and graft survival rates after conversion were 76.5% versus 78.2% and 93.3% versus 86.2, respectively. Overall, there were 12 deaths (3 in G1 and 9 in G2) and 14 graft losses (7 in each group). The causes of death included infection (1 in G1 and 5 in G2) and cardiovascular disease (2 in G1 and 3 in G2). Thirteen grafts were lost due to chronic allograft nephropathy (7 in G1 and 6 in G2) and 1 due to refractory severe acute rejection in G2. Ten patients in G1 (19%) and 24 in G2 (27%) had their immunosuppressive regimen changed, either in the frequency of cyclosporine administration or from cyclosporine to another drug. There were 9 lost to follow-up (4 in G1 and 5 in G2).
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Fig 3. Patient and graft survival after conversion to NEO. Open circles and triangles are patient and solid circles and triangles are graft survival in single- (G1) and twice- (G2) daily cyclosporine dose groups, respectively (P ⬎ .05).
In the long-term follow-up, either cyclosporine overdosing or underdosing likely would produce a detrimental effect on graft function in these patients. It has been described that patients with poor or progressive deteriorating allograft function benefit from cyclosporine dose reduction or cyclosporine withdrawal suggesting that, at least in part or in a fraction of these patients, cyclosporine overdosing is involved.37– 42 Moreover, stable kidney transplant patients receiving NEO underwent safe and effective cyclosporine dose reduction upon changing monitoring strategy from trough to C2 concentrations, suggesting that these patients may have been overdosed.43 The maintenance on a QD schedule appeared to have minimized graft toxicity and preserved function because, although showing worse graft function at the time of conversion to NEO, no significant differences were observed comparing the rate of creatinine increment with that seen in the BID group. Moreover, the rate of function loss was slower in the G1 compared to the G2 group. On the other hand, cyclosporine underdosing has been associated with chronic allograft nephropathy.44 – 46 The lack of acute rejection and the similar rate of graft loss due to chronic allograft nephropathy compared to a relatively lower risk population (G2) support the idea that the dosing frequency was effective in preventing acute rejection and allograft loss. The critical issue related to the safety and efficacy of this strategy is the cyclosporine concentration in each group. First, G2 patients showed typical C12 whole blood cyclosporine trough concentrations, receiving either SIM or NEO (Table 3; Fig 2). While on SIM, G1 patients showed worse graft function but significantly lower cyclosporine C24 concentrations, making a direct comparison between the
two groups difficult to interpret. Bunke et al showed an improvement in glomerular filtration rate in cardiac transplant recipients switched from BID to QD schedule.47 The criticism was that the benefit observed was due to reduction in drug absorption and reduced trough concentrations.48 Johnston and Holt stated that to compare the renal function of patients on QD and BID dosing schedules the patients should have been dosed to the same trough cyclosporine concentration.48 Although our transplant population was dosed to and benefited from a lower trough concentration for 50 months while on single daily doses of SIM, after conversion to NEO there were no differences between QD and BID, validating a direct comparison of the effect of the two treatment schedules on long-term graft function. After conversion, patients in G1 showed an increase in cyclosporine concentration, probably due to increased absorption, reaching similar concentrations to that seen in G2 group, although still receiving significantly lower cyclosporine doses. This behavior can be explained by better improvement in absorption in G1 compared to G2, because after the conversion to NEO dose-normalized cyclosporine concentration showed a higher increase in G1 compared to G2 (Table 3). Schadeli et al observed similar findings analyzing steady-state pharmacokinetics or once-daily cyclosporine in 60 stable renal transplant recipients before and after conversion from SIM to NEO. This group suggested that, after the administration of higher single daily doses, the rapid formation of readily absorbable microemulsion results in rapid absorption and a short residence time in a small “absorption time window” in the gut, reducing exposure to gut first-pass metabolism and result-
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ing in better dose linearity49,50 It also was suggested that QD would result in a higher peak and peak/trough concentration ratio leading to toxic effect.48 Although we have not measured peak concentrations systematically, there is no reason to predict that they were not higher in QD versus BID. Taking into consideration baseline demographics, we would anticipate that these patients showing higher cyclosporine concentration after conversion to NEO would be at risk for nephrotoxicity after a 1:1 conversion ratio.29 Nonetheless, no detrimental effect was observed during a 5-year follow-up under similar cyclosporine dose reductions and cyclosporine C24 and C12 trough concentrations, and, in fact, a slower rate of function graft loss was observed in the QD group (Fig 1). Two main reasons may be involved in this result. First, patients in G1 may have benefited from higher peak concentrations, currently associated with better outcomes51 and may have been protected from nephrotoxicity because a QD schedule allows “drug holiday”31,32 which may be associated with a lower frequency of daily cyclosporineinduced hypoperfusion52 and superior systemic and hemodynamic profiles.53 Another possibility is the reduced intrapatient variability observed in G1 after conversion to NEO, which has been associated with superior long-term graft survival.23 The pattern of cyclosporine concentration changes of this study is supported by a recent detailed pharmacokinetic study in patients receiving single daily doses of cyclosporine switched to NEO.50 The rate of changes in immunosuppression cannot be implicated in these findings because higher percentage of changes were seen in G2, mainly due to conversion from a BID to a QD NEO schedule. Maximal inhibition of calcineurin correlates directly with peak cyclosporine blood concentrations and with efficacy in retrospective and prospective clinical trials.54 Neither the extent nor the duration of inhibition required to produce immunosuppression, however, have been directly assessed. Moreover, it has not been determined yet whether two daily cycles of calcineurin inhibition, diurnal and nocturnal, are required to produce adequate immunosuppression either in short-term or long-term follow-up because NEO is prescribed twice daily due to pharmacokinetic and not to pharmacodynamic reasons. If two peak concentrations were required to produce adequate immunosuppression, it would be advisable to monitor the nocturnal C2 because circadian variation, timing of prednisone dose and meals,22 and drug coadministration, such as sirolimus,55 have been described to be associated with significantly reduced nocturnal peak concentrations. Although long-term graft survival has been achieved with QD SIM56,57 this study is the first to demonstrate that this strategy also may be used with NEO. Whether single daily doses of NEO can produce comparable or superior therapeutic efficacy/toxicity profile compared to the traditional BID schedule when used early after transplantation is not known yet but unquestionably this issue deserves further
SAMPAIO, PARK, FELIPE ET AL
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