Tacrolimus (Page 10 of 16)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).

Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

12.3 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 transplant, and heart transplant patients ( Table 17).

Table 17. Pharmacokinetics Parameters (mean ± S.D.) of Tacrolimus in Healthy Volunteers and Patients

Population N Route (Dose) Parameters
C max (ng/mL) T max (hr) AUC (ng•hr/mL) t 1/2 (hr) CI (L/hr/kg) V (L/kg)
Healthy Volunteers 8 IV (0.025 mg/kg/4 hr) * * 652 ± 156 34.2 ± 7.7 0.040 ± 0.009 1.91 ± 0.31
30 PO (5 mg) (granules) 35.6 ± 10.9 1.3 ± 0.5 320 ± 164 32.1 ± 5.9
PO (5 mg) (capsules) 28.8 ± 8.9 1.5 ± 0.7 266 ± 95 32.3 ± 8.8
Kidney Transplant Patients 26 IV (0.02 mg/kg/12 hr) * * 294 ± 262 18.8 ± 16.7 0.083 ± 0.05 1.41 ± 0.66
PO (0.2 mg/kg/day) 19.2 ± 10.3 3 203 ± 42
PO (0.3 mg/kg/day) 24.2 ± 15.8 1.5 288 ± 93
Liver Transplant Patients 17 IV (0.05 mg/kg/12 hr) * * 3300 ± 2130 11.7 ± 3.9 0.053 ± 0.017 0.85 ± .30
PO (0.3 mg/kg/day) 68.5 ± 30.0 2.3 ± 1.5 519 ± 179
Heart Transplant Patients 11 IV (0.01 mg/kg/day as a continuous infusion) * * 954 § ± 334 23.6 ± 9.22 0.051 ± 0.015
11 PO (0.075 mg/kg/day)¶ 14.7 ± 7.79 2.1 [0.5-6.0] # 82.7 Þ ± 63.2 *
14 PO (0.15 mg/kg/day)¶ 24.5 ± 13.7 1.5 [0.4-4.0] # 142 Þ ± 116 *

* not applicable

† AUC0-inf

‡ not available

§ AUC0-t

¶ Determined after the first dose

# Median [range]
Þ 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 patients (N = 11) and 18 ± 5% in healthy volunteers (N = 16).

A single dose trial conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose trial in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (C max ) 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 10-12 hours post-dose (C min ) 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. In 25 heart transplant patients over a concentration range of 2 to 24 ng/mL, the correlation coefficient was 0.89 after an oral dose of 0.075 or 0.15 mg/kg/day at steady-state.

In a healthy volunteer adult study, the systemic exposure to tacrolimus (AUC) for tacrolimus Granules was approximately 16% higher than that for tacrolimus capsules when administered as single doses. If pediatric patients are converted between formulations, therapeutic drug monitoring must be performed and dose adjustments made to ensure that systemic exposure to tacrolimus is maintained.

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 C max were decreased 37% and 77%, respectively; T max was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max 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 C max was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition.

When administered 1.5 hours following the meal, mean C max was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.

In 11 liver transplant patients, tacrolimus administered 15 minutes after a high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27 ± 18%) and C max (50 ± 19%), as compared to a fasted state.

Tacrolimus capsules, USP should be taken consistently every day either with or without food because the presence and composition of food decreases the bioavailability of tacrolimus [see Dosage and Administration ( 2.1)].

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5-50 ng/mL. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein, and has a high level of association with erythrocytes. The distribution of tacrolimus between whole blood and plasma depends on several factors, such as hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a U.S. trial, the ratio of whole blood concentration to plasma concentration averaged 35 (range 12 to 67).

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