Renal and Hepatic Insufficiency

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

Population
(No. of Patients) Dose AUC0 to 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 mgPO 488 ± 320
(t=72 hr) 66.1 ± 44.8
Range: 29.5 to 138 3.7 ± 4.7a  0.034 ± 0.019a 
Severe Hepatic Impairment
(n=6, IV) 0.02 mg/kg/4hr
IV (n=2)
0.01mg/kg/8hr
IV (n=4) 762 ± 204
(t=120 hr)
289±117
(t=144 hr) 198 ± 158
Range:81to 436 3.9 ± 1.0 0.017 ± 0.013
(n=5, PO)b  8 mg PO
(n=1)
5 mg PO
(n=4)
4 mg PO
(n=1) 658
(t=120 hr)
533±156
(t=144 hr) 119 ± 35
Range: 85 to 178 3.1 ± 3.4a  0.016 ± 0.011a 

a) corrected for bioavailability

b) 1 patient did not receive the PO dose

Renal Insufficiency: Tacrolimus pharmacokinetics following a single IV administration were determined in 12 patients (7 not on dialysis and 5 on dialysis, serum creatinine of 3.9±1.6 and 12.0±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 (see previous table).

Hepatic Insufficiency: 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 6 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.

Race

A formal study to eva luate the pharmacokinetic disposition of tacrolimus in Black transplant patients has not been conducted. However, a retrospective comparison of Black and Caucasian kidney transplant patients indicated that Black patients required higher tacrolimus doses to attain similar trough concentrations. (See DOSAGE AND ADMINISTRATION. )

Gender

A formal study to eva luate 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 and liver transplant patients indicated no gender-based differences.

CLINICAL STUDIES
Liver Transplantation
The safety and efficacy of tacrolimus-based immunosuppression following orthotopic liver transplantation were assessed in two prospective, randomized, non-blinded multicenter studies. The active control groups were treated with a cyclosporine-based immunosuppressi