Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the 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.
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 transplant, and heart transplant patients (Table 14).
|Cm a x ( ng / mL )||Tm a x ( hr )||AUC ( ng • hr / mL )||t1 / 2 ( hr )||Cl ( L / hr / kg )||V ( L / kg )|
|HealthyVolunteers||8||IV(0.025 mg/kg/4hr)||*||*||598†± 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||243‡± 73||34.8± 11.4||0.041§± 0.008||1.94§± 0.53|
|KidneyTransplantPatients||26||IV(0.02 mg/kg/12hr)||*||*||294¶± 262||18.8± 16.7||0.083± 0.050||1.41± 0.66|
|PO(0.2 mg/kg/day)||19.2± 10.3||3||203#± 42||Þ||Þ||Þ|
|PO(0.3 mg/kg/day)||24.2± 15.8||1.5||288ß± 93||Þ||Þ||Þ|
|LiverTransplantPatients||17||IV(0.05 mg/kg/12hr)||*||*||3300à± 2130||11.7± 3.9||0.053± 0.017||0.85± 0.30|
|PO(0.3 mg/kg/day)||68.5± 30||2.3± 1.5||519 ± 179||Þ||Þ||Þ|
|Heart Transplant Patients||11||IV(0.01 mg/kg/day as a continuous infusion)||*||*||954è± 334||23.6± 9.22||0.051± 0.015||Þ|
|11||PO(0.075 mg/kg/day)ð||14.7 + 7.79||2.1 [0.5-6.0]ø||82.7ý± 63.2||*||Þ||Þ|
|14||PO(0.15 mg/kg/day)ð||24.5 ± 13.7||1.5 [0.4-4.0]ø||142ý ± 116||*||Þ||Þ|
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.
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