Tacrolimus (Page 11 of 16)

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, 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 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 Patients

Tacrolimus 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 Cmax 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 Dosage and Administration ( 2.3)].

Tacrolimus Granules Pharmacokinetics in Pediatric Patients

A multicenter, open-label, single arm, pharmacokinetic study (OPTION, NCT01371331) was conducted using tacrolimus granules for oral suspension in pediatric patients undergoing de novo liver, kidney, or heart transplant. After an initial 24­ hour continuous IV infusion of tacrolimus (0.025 mg/kg/hour) for 12 hours to 4 days, oral Tacrolimus Granules were dosed at 0.3 mg/kg/day in divided doses twice daily. Tacrolimus whole blood trough concentrations ranged from 5-15 ng/mL for the first month post-transplant, and 5-10 ng/mL thereafter. Two pharmacokinetic (PK) profiles, AUC, C max , T max and C trough , were taken after the first oral dose (Day 1) and at steady state (Day 7). Subsequent oral doses of Tacrolimus Granules were adjusted based on clinical evidence of efficacy, the whole-blood trough levels, and/or occurrence of adverse events. Of 52 patients enrolled, thirty-eight (38) had evaluable PK profile. The mean pediatric age was 6.1 years for heart transplant, 1.1 years for liver transplant and 3.6 years for kidney transplant. Summary results of PK parameters are presented in Table 18.

Table 18. Summary of Whole Blood PK Parameters of Tacrolimus after Administration of Tacrolimus Granules in Pediatric Patients

Population N (age range) Parameters
AUC tau [hr*ng/mL] mean ± SD C max [ng/mL] mean ± SD T max [hr] mean ± S D Ctrough [ng/mL] mean ± SD
Heart Transplant Patients 12 (0.58-13 years) Day 1 Day 7 224.13 ± 114.30 165.17 ± 39.12 45.61 ± 19.55 32.69 ± 9.78 2.95 ± 4.33 0.84 ± 0.44 12.60 ± 13.40 7.57 ± 1.80
Liver Transplant Patients 14 (0.33-12 years) Day 1 Day 7 210.56 ± 84.01 195.08 ± 94.63 25.11 ± 10.78 30.52 ± 19.35 2.73 ± 1.84 1.71 ± 1.12 13.41 ± 7.11 9.71 ± 4.03
Kidney Transplant Patients 12 (2.42-11 years) Day 1 Day 7 97.40 ± 36.77 208.32 ± 68.75 18.04 ± 8.10 36.63 ± 13.97 1.78 ± 0.88 1.09 ± 0.61 3.54 ± 1.45 8.92 ± 3.59
Renal and Hepatic Impaired Patients

The mean pharmacokinetic parameters for tacrolimus following single administrations to adult patients with renal and hepatic impairment are given in Table 19.

Table 19. Pharmacokinetics in Renal and Hepatic Impaired Adult Patients

Population (No. of Patients) Dose AUC 0-t (ng-hr/mL) t 1/2 (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: 27.8-141 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/4hr IV (n=2) 762±204 (t=120hr) 198±158 Range: 81-436 3.9±1.0 0.017±0.013
0.01 mg/kg/8hr 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)

*corrected for bioavailability

†1 patient did not receive the PO dose

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