Tacrolimus: Package Insert and Label Information (Page 8 of 11)

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 mg, 7 mg, and 10 mg.

In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10 to 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.

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 (2.5)].

Distribution

The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of 5 to 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).

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 eight 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, and 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 six healthy volunteers, the mean recovery of radiolabel was 77.8 ± 12.7%. Fecal elimination accounted for 92.4 ± 1% 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 0.172 ± 0.088 L/hr/kg.

Specific Populations

Pediatric

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 nine 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%.

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 Dosage and Administration (2.2)].

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 (range 0.06 to 0.09) mg/kg/day to 12 pediatric patients (eight male and four female), mean terminal half-life and clearance were 10.2 ± 5 (range 3.4 to 25) hours and 0.12 ± 0.04 (range 0.06 to 0.17) L/hr/kg, respectively. Following oral administration to the same patients, mean AUC and C_max were 181 ± 65 (range 81 to 300) ng•hr /mL and 30 ± 11 (range 14 to 49) ng/mL, respectively. The absolute bioavailability was 19 ± 14 (range 5.2 to 56) %.

Renal and Hepatic Impairment

The mean pharmacokinetic parameters for tacrolimus following single administrations to patients with renal and hepatic impairment are given in Table 15.

Table 15. Pharmacokinetic In Renal and Hepatic Impaired Patients

* corrected for bioavailability † one patient did not receive the PO dose
Population (No. of Patients)	Dose	AUC0-t (ng•hr/mL)	t1/2 (hr)	V (L/kg)	CI (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 to 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 to 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 to 436	3.9 ± 1	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 to 178	3.1 ± 3.4*	0.016 ± 0.011*
	5 mg PO (n = 4)	533 ± 156 (t = 144 hr)
	4 mg PO (n = 1)

Renal Impairment

Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (seven not on dialysis and five on dialysis, serum creatinine of 3.9 ± 1.6 and 12 ± 2.4 mg/dL, respectively) prior to their kidney transplant. The pharmacokinetic parameters obtained were similar for both groups. The mean clearance of tacrolimus in patients with renal dysfunction was similar to that in normal volunteers (Table 15) [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)].

Hepatic Impairment

Tacrolimus pharmacokinetics have been determined in six patients with mild hepatic dysfunction (mean Pugh score: 6.2) following single IV and oral administrations. The mean clearance of tacrolimus in patients with mild hepatic dysfunction was not substantially different from that in normal volunteers (see previous table). Tacrolimus pharmacokinetics were studied in six patients with severe hepatic dysfunction (mean Pugh score: > 10). The mean clearance was substantially lower in patients with severe hepatic dysfunction, irrespective of the route of administration [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].

Race

The pharmacokinetics of tacrolimus have been studied following single IV and oral administration of tacrolimus to ten African-American, 12 Latino-American, and 12 Caucasian healthy volunteers. There were no significant pharmacokinetic differences among the three ethnic groups following a 4 hour IV infusion of 0.015 mg/kg. However, after single oral administration of 5 mg, mean (± SD) tacrolimus C_max in African-Americans (23.6 ± 12.1 ng/mL) was significantly lower than in Caucasians (40.2 ± 12.6 ng/mL) and the Latino-Americans (36.2 ± 15.8 ng/mL) (p < 0.01). Mean AUC_0-inf tended to be lower in African-Americans (203 ± 115 ng•hr/mL) than Caucasians (344 ± 186 ng•hr/mL) and Latino-Americans (274 ± 150 ng•hr/mL). The mean (± SD) absolute oral bioavailability (F) in African-Americans (12 ± 4.5%) and Latino-Americans (14 ± 7.4%) was significantly lower than in Caucasians (19 ± 5.8%, p = 0.011). There was no significant difference in mean terminal T_1/2 among the three ethnic groups (range from approximately 25 to 30 hours). A retrospective comparison of African-American and Caucasian kidney transplant patients indicated that African-American patients required higher tacrolimus doses to attain similar trough concentrations [see Dosage and Administration (2.1)].

Gender

A formal trial to evaluate the effect of gender on tacrolimus pharmacokinetics has not been conducted, however, there was no difference in dosing by gender in the kidney transplant trial. A retrospective comparison of pharmacokinetics in healthy volunteers, and in kidney, liver and heart transplant patients indicated no gender-based differences.

Drug Interactions

Frequent monitoring of whole blood concentrations and appropriate dosage adjustments of tacrolimus are recommended when concomitant use of the following drugs with tacrolimus is initiated or discontinued [see Drug Interactions (7)].

Telaprevir

In a single dose study in nine healthy volunteers, co-administration of tacrolimus (0.5 mg single dose) with telaprevir (750 mg 3 times daily for 13 days) increased the tacrolimus dose-normalized C_max by 9.3-fold and AUC by 70-fold compared to tacrolimus alone [see Drug Interactions (7.3)].

Boceprevir

In a single dose study in 12 subjects, co-administration of tacrolimus (0.5 mg single dose) with boceprevir (800 mg 3 times daily for 11 days) increased tacrolimus C_max by 9.9-fold and AUC by 17-fold compared to tacrolimus alone [see Drug Interactions (7.3)].

Nelfinavir

Based on a clinical study of five liver transplant recipients, co-administration of tacrolimus with nelfinavir increased blood concentrations of tacrolimus significantly and, as a result, a reduction in the tacrolimus dose by an average of 16-fold was needed to maintain mean trough tacrolimus blood concentrations of 9.7 ng/mL. It is recommended to avoid concomitant use of tacrolimus and nelfinavir unless the benefits outweigh the risks [see Drug Interactions (7.3)].

Rifampin

In a study of six normal volunteers, a significant decrease in tacrolimus oral bioavailability (14 ± 6% vs. 7 ± 3%) was observed with concomitant rifampin administration (600 mg). In addition, there was a significant increase in tacrolimus clearance (0.036 ± 0.008 L/hr/kg vs. 0.053 ± 0.010 L/hr/kg) with concomitant rifampin administration [see Drug Interactions (7.7)].