e dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.
In animals, Tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen-induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.
Pharmacokinetics
Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of Tacrolimus have been determined following intravenous (IV) and/or oral (PO) administration in healthy volunteers, and in kidney transplant, liver and heart transplant patients (Table 14).
Table 14. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients
Population N Route (Dose) Parameters
Cmax (ng/mL) Tmax (hr) AUC (ng•hr/mL) t1/2 (hr) CI (L/hr/kg) V (L/kg)
Healthy Volunteers 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
Kidney Transplant Patients 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
Liver Transplant Patients 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
Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) a a 954g ± 334 23.6 ± 9.22 0.051 ± 0.015 f
11 PO (0.075 mg/kg/day)h 14.7 ± 7.79 2.1 [0.5-6.0]i 82.7j ± 63.2 a f f
14 PO(0.15 mg/kg/day)h 24.5 ±13.7 1.5 [0.4-4.0]i 142j ± 116 a f f
a) not applicable
b) AUC0-120
c) AUC0-72
d) Corrected for individual bioavailability
e) AUC0-inf
f) not available
g) AUC0-t
h) Determined after the first dose
i) Median [range]
j) AUC0-12
Due to intersubject variability in Tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy [see Dosage and Administration (2.6)]. 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), 23±9% in adult heart transplant
