Tacrolimus (Page 12 of 17)
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.
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 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).
Elimination
Metabolism
Tacrolimus is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P-450 system (CYP3A). A metabolic pathway leading to the formation of 8 possible metabolites has been proposed. Demethylation and hydroxylation were identified as the primary mechanisms of biotransformation in vitro. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.
Excretion
The mean clearance following IV administration of tacrolimus is 0.040, 0.083, 0.053, and 0.051 L/hr/kg in healthy volunteers, adult kidney transplant patients, adult liver transplant patients, and adult heart transplant patients, respectively. In man, less than 1% of the dose administered is excreted unchanged in urine.
In a mass balance study of IV-administered radiolabeled tacrolimus to 6 healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1.0% and the elimination half-life based on radioactivity was 48.1 ± 15.9 hours whereas it was 43.5 ± 11.6 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.029 ± 0.015 L/hr/kg and clearance of tacrolimus was 0.029 ± 0.009 L/hr/kg. When administered PO, the mean recovery of the radiolabel was 94.9 ± 30.7%. Fecal elimination accounted for 92.6 ± 30.7%, urinary elimination accounted for 2.3 ± 1.1% and the elimination half-life based on radioactivity was 31.9 ± 10.5 hours whereas it was 48.4 ± 12.3 hours based on tacrolimus concentrations. The mean clearance of radiolabel was 0.226 ± 0.116 L/hr/kg and clearance of tacrolimus was 0.172 ± 0.088 L/hr/kg.
Specific Populations
Pediatric Patients
Tacrolimus Capsules Pharmacokinetics in Pediatric Patients
Pharmacokinetics of tacrolimus have been studied in liver transplantation patients, 0.7 to 13.2 years of age. Following IV administration of a 0.037 mg/kg/day dose to 12 pediatric patients, mean terminal half-life, volume of distribution and clearance were 11.5 ± 3.8 hours, 2.6 ± 2.1 L/kg and 0.138 ± 0.071 L/hr/kg, respectively. Following oral administration to 9 patients, mean AUC and C max were 337 ± 167 ng•hr/mL and 48.4 ± 27.9 ng/mL, respectively. The absolute bioavailability was 31 ± 24%.
Pharmacokinetics of tacrolimus have also been studied in kidney transplantation patients, 8.2 ± 2.4 years of age. Following IV infusion of a 0.06 mg/kg/day to 12 pediatric patients (8 male and 4 female), mean terminal half-life and clearance were 10.2 ± 5.0 hours and 0.12 ± 0.04 L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C max were 181 ± 65 ng•hr/mL and 30 ± 11 ng/mL, respectively. The absolute bioavailability was 19 ± 14%.
Whole blood trough concentrations from 31 patients less than 12 years old showed that pediatric patients needed higher doses than adults to achieve similar tacrolimus trough concentrations [see Error! Hyperlink reference not valid. ].
Renal and Hepatic Impairment
The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19.
| Population (No. of Patients) | Dose | AUC 0-t (ng•hr/mL) | t 1/2 (hr) | V (L/kg) | CL (L/hr/kg) |
| Renal Impairment (n = 12) | 0.02 mg/kg/4 hr IV | 393 ± 123 (t = 60 hr) | 26.3 ± 9.2 | 1.07 ± 0.20 | 0.038 ± 0.014 |
| Mild Hepatic Impairment (n = 6) | 0.02 mg/kg/4 hr IV | 367 ± 107 (t = 72 hr) | 60.6 ± 43.8 Range: 27.8 ˗ 141 | 3.1 ± 1.6 | 0.042 ± 0.02 |
| 7.7 mg PO | 488 ± 320 (t = 72 hr) | 66.1 ± 44.8 Range: 29.5˗138 | 3.7 ± 4.7 * | 0.034 ± 0.019 * | |
| Severe Hepatic Impairment (n = 6, IV) | 0.02 mg/kg/4 hr IV (n = 2) | 762 ± 204 (t = 120 hr) | 198 ± 158 Range:81 ˗ 436 | 3.9 ± 1.0 | 0.017 ± 0.013 |
| 0.01 mg/kg/8 hr IV (n = 4) | 289 ± 117 (t = 144 hr) | ||||
| (n = 5, PO) † | 8 mg PO (n = 1) | 658 (t = 120 hr) | 119 ± 35 Range: 85 ˗ 178 | 3.1 ± 3.4 * | 0.016 ± 0.011 * |
| 5 mg PO (n = 4) | 533 ± 156 (t = 144 hr) | ||||
| 4 mg PO (n = 1) | |||||
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