Tacrolimus (Page 2 of 7)

CLINICAL STUDIES

Liver Transplantation

The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressive regimen. Both studies used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These studies were designed to evaluate whether the two regimens were therapeutically equivalent, with patient and graft survival at 12 months following transplantation as the primary endpoints. The tacrolimus-based immunosuppressive regimen was found to be equivalent to the cyclosporine-based immunosuppressive regimens.

In one trial, 529 patients were enrolled at 12 clinical sites in the United States; prior to surgery, 263 were randomized to the tacrolimus-based immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used, while 2 sites used different control protocols. This trial excluded patients with renal dysfunction, fulminant hepatic failure with Stage IV encephalopathy, and cancers; pediatric patients (≤ 12 years old) were allowed.

In the second trial, 545 patients were enrolled at 8 clinical sites in Europe; prior to surgery, 270 were randomized to the tacrolimus-based immunosuppressive regimen and 275 to CBIR. In this study, each center used its local standard CBIR protocol in the active-control arm. This trial excluded pediatric patients, but did allow enrollment of subjects with renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy, and cancers other than primary hepatic with metastases.

One-year patient survival and graft survival in the tacrolimus-based treatment groups were equivalent to those in the CBIR treatment groups in both studies. The overall 1-year patient survival (CBIR and tacrolimus-based treatment groups combined) was 88% in the U.S. study and 78% in the European study. The overall 1-year graft survival (CBIR and tacrolimus-based treatment groups combined) was 81% in the U.S. study and 73% in the European study. In both studies, the median time to convert from IV to oral tacrolimus dosing was 2 days.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Kidney Transplantation

Tacrolimus/azathioprine

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a Phase 3 randomized, multicenter, non-blinded, prospective study. There were 412 kidney transplant patients enrolled at 19 clinical sites in the United States. Study therapy was initiated when renal function was stable as indicated by a serum creatinine ≤ 4 mg/dL (median of 4 days after transplantation, range 1 to 14 days). Patients less than 6 years of age were excluded.

There were 205 patients randomized to tacrolimus-based immunosuppression and 207 patients were randomized to cyclosporine-based immunosuppression. All patients received prophylactic induction therapy consisting of an antilymphocyte antibody preparation, corticosteroids and azathioprine. Overall 1 year patient and graft survival was 96.1% and 89.6%, respectively and was equivalent between treatment arms.

Because of the nature of the study design, comparisons of differences in secondary endpoints, such as incidence of acute rejection, refractory rejection or use of OKT3 for steroid-resistant rejection, could not be reliably made.

Tacrolimus/mycophenolate mofetil (MMF)

Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multi-center trial (Study 1), 1589 kidney transplant patients received tacrolimus (Group C, n=401), sirolimus (Group D, n=399), or one of two cyclosporine regimens (Group A, n=390 and Group B, n=399) in combination with MMF and corticosteroids; all patients, except those in one of the two cyclosporine groups, also received induction with daclizumab. The study was conducted outside the United States; the study population was 93% Caucasian. In this study, mortality at 12 months in patients receiving tacrolimus/MMF was similar (2.7%) compared to patients receiving cyclosporine/MMF (3.3% and 1.8%) or sirolimus/MMF (3.0%). Patients in the tacrolimus group exhibited higher estimated creatinine clearance rates (eCLcr ) using the Cockcroft-Gault formula (Table 1) and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up (Table 2) in comparison to each of the other three groups. Patients randomized to tacrolimus/MMF were more likely to develop diarrhea and diabetes after the transplantation and experienced similar rates of infections compared to patients randomized to either cyclosporine/MMF regimen (see ADVERSE REACTIONS).

Table 1: Estimated Creatinine Clearance at 12 Months in Study 1
Group eCLcr [mL/min] at Month 12 a
N MEAN SD MEDIAN Treatment Difference with Group C (99.2% CI b)
Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus
a) All death/graft loss (n=41, 27, 23 and 42 in Groups A, B, C and D) and patients whose last recorded creatinine values were prior to month 3 visit (n=10, 9, 7 and 9 in Groups A, B, C and D) were inputed with GFR of 10 mL/min; a subject’s last observed creatinine value from month 3 on was used for the remainder of subjects with missing creatinine at month 12 (n=11, 12, 15 and 19 for Groups A, B, C and D). Weight was also imputed in the calculation of estimated GFR, if missing.
b) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
(A) CsA/MMF/CS 390 56.5 25.8 56.9 -8.6 (-13.7, -3.7)
(B) CsA/MMF/CS/Daclizumab 399 58.9 25.6 60.9 -6.2 (-11.2, -1.2)
(C) Tac/MMF/CS/Daclizumab 401 65.1 27.4 66.2 -
(D) Siro/MMF/CS/Daclizumab 399 56.2 27.4 57.3 -8.9 (-14.1, -3.9)
Total 1589 59.2 26.8 60.5
Table 2: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 1
AN=390 BN=399 CN=401 DN=399
Group A =CsA/MMF/CS, B =CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab
a) Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.
Overall Failure 141 (36.2%) 126 (31.6%) 82 (20.4%) 185 (46.4%)
Components of efficacy failure
BPAR 113 (29.0%) 106 (26.6%) 60 (15.0%) 152 (38.1%)
Graft loss excluding death 28 (7.2%) 20 (5.0%) 12 (3.0%) 30 (7.5%)
Mortality 13 (3.3%) 7 (1.8%) 11 (2.7%) 12 (3.0%)
Lost to follow-up 5 (1.3%) 7 (1.8%) 5 (1.3%) 6 (1.5%)
Treatment Difference of efficacy failure compared toGroup C (99.2% CIa) 15.8% (7.1%,24.3%) 11.2% (2.7%,19.5%) - 26.0% (17.2%,34.7%)

The protocol-specified target tacrolimus trough concentrations (Ctrough ,Tac) were 3 to 7 ng/mL; however, the observed median Ctroughs ,Tac approximated 7 ng/mL throughout the 12 month study (Table 3).

Table 3: Tacrolimus Whole Blood Trough Concentrations (Study 1)
Time Median (P10-P90a) tacrolimus whole blood trough concentrations(ng/mL)
a) Range of Ctrough ,Tac that excludes lowest 10% and highest 10% of Ctrough ,Tac
Day 30 (N=366) 6.9 (4.4 to 11.3)
Day 90 (N=351) 6.8 (4.1 to 10.7)
Day 180 (N=355) 6.5 (4.0 to 9.6)
Day 365 (N=346) 6.5 (3.8 to 10.0)

The protocol-specified target cyclosporine trough concentrations (Ctrough ,CsA) for Group B were 50 to 100 ng/mL; however, the observed median Ctroughs ,CsA approximated 100 ng/mL throughout the 12 month study. The protocol-specified target Ctroughs ,CsA for Group A were 150 to 300 ng/mL for the first 3 months and 100 to 200 ng/mL from month 4 to month 12; the observed median Ctroughs ,CsA approximated 225 ng/mL for the first 3 months and 140 ng/mL from month 4 to month 12.

While patients in all groups started MMF at 1g BID, the MMF dose was reduced to <2 g/day in 63% of patients in the tacrolimus treatment arm by month 12 (Table 4); approximately 50% of these MMF dose reductions were due to adverse events. By comparison, the MMF dose was reduced to <2 g/day in 49% and 45% of patients in the two cyclosporine arms (Group A and Group B, respectively), by month 12 and approximately 40% of MMF dose reductions were due to adverse events.

Table 4: MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)
Time period Time-averaged MMF dose (g/day)a
(Days) <2.0 2.0 >2.0
Time-averaged MMF dose = (total MMF dose)/(duration of treatment)
a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two g/day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
0 to 30 (N=364) 37% 60% 2%
0 to 90 (N=373) 47% 51% 2%
0 to 180 (N=377) 56% 42% 2%
0 to 365 (N=380) 63% 36% 1%

In a second randomized, open-label, multi-center trial (Study 2), 424 kidney transplant patients received tacrolimus (n=212) or cyclosporine (n=212) in combination with MMF 1 gram BID, basiliximab induction, and corticosteroids. In this study, the rate for the combined endpoint of biopsy proven acute rejection, graft failure, death, and/or lost to follow-up at 12 months in the tacrolimus/MMF group was similar to the rate in the cyclosporine/MMF group. There was, however, an imbalance in mortality at 12 months in those patients receiving tacrolimus/MMF (4.2%) compared to those receiving cyclosporine/MMF (2.4%), including cases attributed to overimmunosuppression (Table 5).

Table 5: Incidence of BPAR, Graft Loss, Death or Loss to Follow-up at 12 Months in Study 2
Tacrolimus/MMF(n=212) Cyclosporine/MMF(n=212)
a) 95% confidence interval calculated using Fisher’s Exact Test
Overall Failure 32 (15.1%) 36 (17.0%)
Components of efficacy failure
BPAR 16 (7.5%) 29 (13.7%)
Graft loss excluding death 6 (2.8%) 4 (1.9%)
Mortality 9 (4.2%) 5 (2.4%)
Lost to follow-up 4 (1.9%) 1 (0.5%)
Treatment Difference of efficacy failure compared to Tacrolimus/MMF group (95% CIa) - 1.9% (-5.2%, 9.0%)

The protocol-specified target tacrolimus whole blood trough concentrations (Ctrough ,Tac) in Study 2 were 7 to 16 ng/mL for the first three months and 5 to 15 ng/mL thereafter. The observed median Ctroughs ,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 (Table 6).

Table 6: Tacrolimus Whole Blood Trough Concentrations (Study 2)
Time Median (P10-P90a) tacrolimus whole blood trough concentrations(ng/mL)
a) Range of Ctrough ,Tac that excludes lowest 10% and highest 10% of Ctrough , Tac
Day 30 (N=174) 10.5 (6.3 to 16.8)
Day 60 (N=179) 9.2 (5.9 to 15.3)
Day 120 (N=176) 8.3 (4.6 to 13.3)
Day 180 (N=171) 7.8 (5.5 to 13.2)
Day 365 (N=178) 7.1 (4.2 to 12.4)

The protocol-specified target cyclosporine whole blood concentrations (Ctrough ,CsA) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median Ctroughs , CsA approximated 280 ng/mL during the first three months and 190 ng/mL from month 4 to month 12.

Patients in both groups started MMF at 1g BID. The MMF dose was reduced to <2 g/day by month 12 in 62% of patients in the tacrolimus/MMF group (Table 7) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse events in the tacrolimus/MMF group and the cyclosporine/MMF group, respectively.

Table 7: MMF Dose Over Time in the Tacrolimus/MMF group (Study 2)
Time period Time-averaged MMF dose (g/day)a
(Days) <2.0 2.0 >2.0
Time-averaged MMF dose=(total MMF dose)/(duration of treatment)
a) Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two g/day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.
0 to 30 (N=212) 25% 69% 6%
0 to 90 (N=212) 41% 53% 6%
0 to 180 (N=212) 52% 41% 7%
0 to 365 (N=212) 62% 34% 4%

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