Tacrolimus (Page 13 of 16)

14 CLINICAL STUDIES

14.1 Kidney Transplantation

Tacrolimus /Azathioprine (AZA)

Tacrolimus-based immunosuppression in conjunction with azathioprine and corticosteroids following kidney transplantation was assessed in a randomized, multicenter, non-blinded, prospective trial. 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.

Data from this trial of tacrolimus in conjunction with azathioprine indicate that during the first 3 months of that trial, 80% of the patients maintained trough concentrations between 7-20 ng/mL, and then between 5-15 ng/mL, through 1 year.

Tacrolimus /Mycophenolate Mofetil (MMF)

Tacrolimus-based immunosuppression in conjunction with MMF, corticosteroids, and induction has been studied. In a randomized, open-label, multicenter trial (Study 1), 1589 kidney transplant patients received Tacrolimus (Group C, n = 401), sirolimus (Group D, n = 399), or one of two cyclosporine (CsA) 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 trial was conducted outside the United States; the trial population was 93% Caucasian. In this trial, mortality at 12 months in patients receiving Tacrolimus/MMF was similar (3%) compared to patients receiving cyclosporine/MMF (3% and 2%) or sirolimus/MMF (3%). Patients in the Tacrolimus group exhibited higher estimated creatinine clearance rates (eCL cr ) using the Cockcroft-Gault formula ( Table 20) and experienced fewer efficacy failures, defined as biopsy-proven acute rejection (BPAR), graft loss, death, and/or lost to follow-up ( Table 21) 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 ( 6.1)].

Table 20. Estimated Creatinine Clearance at 12 Months (Study 1)

Group eCLcr[mL/min] at Month 12*
N MEAN SD MEDIAN Treatment Difference with Group C (99.2%CI†)
(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
Key: CsA=Cyclosporine, CS=Corticosteroids, Tac=Tacrolimus, Siro=Sirolimus

* 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, respectively) were imputed with Glomerular Filtration Rate (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, respectively). Weight was also imputed in the calculation of estimated GFR, if missing.

† Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.

Table 21. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 1)

Group A N=390 Group B N=399 Group C N=401 Group D N=399
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 to Group C 15.8% 11.2% 26.00%
(99.2% CI*) (7.1%, 24.3%) (2.7%, 19.5%) (17.2%, 34.7%)
Key: Group A =CsA/MMF/CS, B =CsA/MMF/CS/Daclizumab, C=Tac/MMF/CS/Daclizumab, and D=Siro/MMF/CS/Daclizumab

*Adjusted for multiple (6) pairwise comparisons using Bonferroni corrections.

The protocol-specified target tacrolimus trough concentrations (C trough,Tac ) were 3-7 ng/mL; however, the observed median C troughs,Tac approximated 7 ng/mL throughout the 12-month trial ( Table 22). Approximately 80% of patients maintained tacrolimus whole blood concentrations between 4-11 ng/mL through 1 year post-transplant.

Table 22. Tacrolimus Whole Blood Trough Concentration Range (Study 1)

Time Median (P10-P90*) tacrolimus whole blood trough concentrations range (ng/mL)
Day 30 (N=366) 6.9 (4.4 – 11.3)
Day 90 (N=351) 6.8 (4.1 – 10.7)
Day 180 (N=355) 6.5 (4.0 – 9.6)
Day 365 (N=346) 6.5 (3.8 – 10.0)

*10 to 90 th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough,Tac

The protocol-specified target cyclosporine trough concentrations (C trough,CsA ) for Group B were 50-100 ng/mL; however, the observed median C troughs,CsA approximated 100 ng/mL throughout the 12 month trial. The protocol-specified target C troughs,CsA for Group A were 150-300 ng/mL for the first 3 months and 100-200 ng/mL from month 4 to month 12; the observed median C troughs,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 1gram twice daily, the MMF dose was reduced to less than 2 g per day in 63% of patients in the tacrolimus treatment arm by month 12 ( Table 23); approximately 50% of these MMF dose reductions were due to adverse reactions. By comparison, the MMF dose was reduced to less than 2 g per 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 reactions.

Table 23: MMF Dose Over Time in Tacrolimus/MMF (Group C) (Study 1)

Time period (Days) Time-averaged MMF dose (grams per day)*
Less than 2.0 2 Greater than 2.0
0-30 (N=364) 37% 60% 2%
0-90 (N=373) 47% 51% 2%
0-180 (N=377) 56% 42% 2%
0-365 (N=380) 63% 36% 1%
Key: Time-averaged MMF dose = (total MMF dose) / (duration of treatment)

* Percentage of patients for each time-averaged MMF dose range during various treatment periods. Administration of 2 g per day of time-averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.

In a second randomized, open-label, multicenter trial (Study 2), 424 kidney transplant patients received Tacrolimus (N = 212) or cyclosporine (N = 212) in combination with MMF 1 gram twice daily, basiliximab induction, and corticosteroids. In this trial, the rate for the combined endpoint of BPAR, graft failure, death, and/or lost to follow-up at 12 months in theTacrolimus /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%) compared to those receiving cyclosporine/MMF (2%), including cases attributed to over-immunosuppression ( Table 24).

T able 24. Incidence of BPAR, Graft Loss, Death, or Loss to Follow-up at 12 Months (Study 2)

Tacrolimus /MMF (n=212) Cyclosporine/MMF (n=212)
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% CI*) 1.9% (-5.2%, 9.0%)

* 95% confidence interval calculated using Fisher’s Exact Test

The protocol-specified target tacrolimus whole blood trough concentrations (C trough,Tac ) in Study 2 were 7-16 ng/mL for the first three months and 5-15 ng/mL thereafter. The observed median C trough,Tac approximated 10 ng/mL during the first three months and 8 ng/mL from month 4 to month 12 ( Table 25). Approximately 80% of patients maintained tacrolimus whole blood trough concentrations between 6 to 16 ng/mL during months 1 through 3 and, then, between 5 to 12 ng/mL from month 4 through 1 year.

Table 25. Tacrolimus Whole Blood Trough Concentration Range (Study 2)

Time Median (P10-P90*) tacrolimus whole blood trough concentrations range (ng/mL)
Day 30 (N=174) 10.5 (6.3 — 16.8)
Day 60 (N=179) 9.2 (5.9 — 15.3)
Day 120 (N=176) 8.3 (4.6 — 13.3)
Day 180 (N=171) 7.8 (5.5 — 13.2)
Day 365 (N=178) 7.1 (4.2 — 12.4)

*a) 10 to 90th Percentile: range of Ctrough,Tac that excludes lowest 10% and highest 10% of Ctrough,Tac

The protocol-specified target cyclosporine whole blood concentrations (C trough,CsA ) were 125 to 400 ng/mL for the first three months, and 100 to 300 ng/mL thereafter. The observed median C troughs , C sA 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 1 gram twice daily. The MMF dose was reduced to less than 2 grams per day by month 12 in 62% of patients in the Tacrolimus/ MMF group (Table 26) and in 47% of patients in the cyclosporine/MMF group. Approximately 63% and 55% of these MMF dose reductions were because of adverse reactions in the Tacrolimus/MMF group and the cyclosporine/MMF group, respectively [see Adverse Reactions ( 6.1)].

Table 26. MMF Dose Over Time in the Tacrolimus/MMF Group (Study 2)

Time Period (Days) Time-averaged MMF dose (g/day)*
Less than 2.0 2 Greater than 2.0
0-30 (N=212) 25% 69% 6%
0-90 (N=212) 41% 53% 6%
0-180 (N=212) 52% 41% 7%
0-365 (N=212) 62% 34% 4%
Key: Time-averaged MMF dose = (total MMF dose) / (duration of treatment)

* Percentage of patients for each time-averaged MMF dose range during various treatment periods. Two grams per day of time- averaged MMF dose means that MMF dose was not reduced in those patients during the treatment periods.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.