Population  N    Route
(Dose)  Parameters 
Cmax
(ng/mL)  Tmax
(hr)  AUC
(ng.hr/mL)  t1/2
(hr)  CI
(L/hr/kg)  V
(L/kg) 
HealthyVolunteers 8 IV (0.025 mg/kg/4hr) a a 598b± 125  34.2± 7.7 0.040± 0.009  1.91±0.31
16 PO (5 mg) 29.7± 7.2 1.6± 0.7 243c± 73 34.8±11.4 0.041d± 0.008 1.94d±0.53
KidneyTransplant Pts 26 IV (0.02 mg/kg/12 hr) a a 294e± 262 18.8±16.7 0.083± 0.050 1.41±0.66
PO (0.2 mg/kg/day) 19.2± 10.3 3.0 203e± 42 f f f
PO (0.3 mg/kg/day) 24.2± 15.8 1.5 288e± 93 f f f
LiverTransplant Pts 17 IV (0.05 mg/kg/12 hr) a a 3300e± 2130 11.7± 3.9 0.053± 0.017 0.85±0.30
PO (0.3 mg/kg/day) 68.5± 30.0 2.3± 1.5 519e± 179 f f f

a) not applicable

b) AUC0 to 120

c) AUC0 to 72

d) Corrected for individual bioavailability

e) Auc0 to inf;

f) not available

Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION ). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.

Absorption

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), and 18±5% in healthy volunteers (N=16).

A single dose study conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose study in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10 to 12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94.

Food Effects

The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.

The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and Cmax were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean Cmax by 28% and 65%, respectively.

In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.