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 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 9 patients, mean AUC and Cmax 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 (8 male and 4 female), mean terminal half-life and clearance were 10.2±5.0 (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 Cmax 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

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/4hr
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/4hr
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±4.7a 0.