Tacrolimus (Page 10 of 16)

11 DESCRIPTION

Tacrolimus is available for oral administration as capsules (Tacrolimus Capsules USP) containing the equivalent of 0.5 mg, 1 mg or 5 mg of tacrolimus USP. Inactive ingredients include anhydrous lactose, hypromellose 2910, croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide.

Tacrolimus, previously known as FK506, is the active ingredient in Tacrolimus Capsules USP. Tacrolimus is a macrolide immunosuppressant produced by Streptomyces tsukubaensis. Chemically, tacrolimus is designated as [3S -[3R *[E (1S *,3S *,4S *)], 4S *,5R *,8S *,9E ,12R *, 14R *,15S *,16R *,18S *,19S *,26aR *]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16- dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c ][1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.

The chemical structure of tacrolimus USP is:

Structural Formula
(click image for full-size original)

Tacrolimus USP has a molecular formula of C44 H69 NO12 •H2 O and a formula weight of 822.03. Tacrolimus appears as white to off white powder. It is soluble in acetone, chloroform, ethyl acetate and insoluble in water.

The Dissolution Test criteria of Tacrolimus Capsules USP as outlined below:

Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mg Complies with USP dissolution test 4

Tacrolimus Capsules USP comply with USP Organic Impurities test criteria as outlined below:

Tacrolimus Capsules USP, 0.5 mg, 1 mg and 5 mg USP Procedure 1 and 2

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following oral (PO) administration in healthy volunteers, and in kidney transplant, liver transplant, and heart transplant patients (Table 14).

Table 14. Pharmacokinetics Parameters (mean±S.D.) of Tacrolimus in Healthy Volunteers and Patients

*
a) not applicable
a) not applicable
b) AUC0-120 ;
§
c) AUC0-72
d) Corrected for individual bioavailability
#
d) Corrected for individual bioavailability
Þ
a) not applicable
ß
a) not applicable
à
e) AUC0-inf ;
è
f) not available
ð
f) not available
ø
f) not available
ý
e) AUC0-inf ;
£
f) not available
¥
f) not available
Œ
f) not available
œ
a) not applicable
Ɖ
a) not applicable
A
e) AUC0-inf ;
B
e) AUC0-inf ;
C
f) not available
D
f) not available
E
f) not available
F
a) not applicable
G
a) not applicable
H
g) AUC0-t
I
f) not available
J
h) Determined after the first dose
K
i) Median [range]
L
j) AUC0-12
M
a) not applicable
N
f) not available
O
f) not available
P
h) Determined after the first dose
Q
i) Median [range]
R
j) AUC0-12
S
a) not applicable
T
f) not available
U
f) not available
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) * 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
Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) Þ ß 294 e± 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 203à± 42 è ð ø
PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288ý± 93 £ ¥ Œ
Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) œ Ɖ 3300A± 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 519B± 179 C D E
Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) F G 954H± 334 23.6 ± 9.22 0.051 ± 0.015 I
11 PO (0.075 mg/kg/day)J 14.7 ± 7.79 2.1 [0.5-6.0]K 82.7L± 63.2 M N O
14 PO (0.15 mg/kg/day)P 24.5 ± 13.7 1.5 [0.4-4.0]Q 142R± 116 S T U

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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