Table 3: Tacrolimus Whole Blood Trough Concentrations (Study 1)

Time  Median (P10-P90 a) tacrolimus whole blood trough concentrations(ng/mL) 
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) 

 
a) Range of Ctrough, Tac that excludes lowest 10% and highest 10% of Ctrough, Tac

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 (Days)  Time-averaged MMF dose (g/day) a 
<2.0 2.0 >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%

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.

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 over immunosuppression (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)
Overall Failure Components of efficacy failure  32 (15.1%)  36 (17.0%) 
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%)

  
a) 95% confidence interval calculated using Fisher's Exact Test

The