reduced 63%, and mean AUC was reduced 39%, relative to the fasted
condition.
In 11 liver transplant patients, Prograf administered 15 minutes after a
high fat (400 kcal, 34% fat) breakfast, resulted in decreased AUC (27± 18%)
and Cmax (50±19%), as compared to a fasted state.
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. study, 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 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 L/hr/kg in healthy volunteers, adult kidney transplant
patients and adult liver 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.
Special 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 43.4±27.9 ng/mL,
respectively. The absolute bioavailability was 31± 21%.
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).
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 |Dose |AUC 0-t |tЅ |V |Cl |
|(No. of | |(ng·hr/mL|(hr) |(L/kg|(L/hr/kg)|
|Patients) | |) | |) | |
|Renal |0.02 |393±123 |26.3±9.2 |1.07 |0.038 |
|Impairment |mg/kg/4h|(t = | | |±0.014 |
|(n=12) |r |60hr) | |±0.20| |
| |IV | | | | |
|Mild Hepatic |0.02 |367±107 |60.6±43.8 |3.1 |0.042 |
|Impairment |mg/kg/4h|(t=72hr) |Range: 27.8 - |±1.6 |±0.02 |
|(n=6) |r | |141 | | |
| |7.7 mg |488±320 |66.1±44.8 |3.7 |0.034 |
| |PO |(t = |Range: 29.5 - |±4.7*|±0.019* |
| | |72hr) |138 | | |
|Severe Hepatic |0.02 |762±204 |198±158 |3.9 |0.017 |
|Impairment |mg/kg/4h|(t=120hr)|Range: 81-436 |±1.0 |±0.013 |
|(n=6, IV) |r | | | | |
| |IV (n=2)| | | | |
| | | | | | |
| |0.01 |289±117 | | | |
| |mg/kg/8h|(t=144hr)| | | |
| |r | | | | |
| |IV (n=4)| | | | |
|Severe Hepatic |8 mg PO |658 |119±35 |3.1 |0.016 |
|Impairment |(n=1) |(t=120hr)|Range: 85-178 |±3.4*|±0.011* |
|(n=5, PO)† | | | | | |
| |5mg PO |533±156 | | | |
| |(n=4) |(t=144hr)| | | |
| |4 mg PO | | | | |
| |(n=1) | | | | |
|* corrected for bioavailability |
|† 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 sever 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 evaluate 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 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 and
liver transplant patients indicated no gender-based differences.
Clinical Studies
Liver Transplantation
The safety and efficacy of Prograf-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 immunosuppressive regimen. Both studies
used concomitant adrenal corticosteroids as part of the immunosuppressive
regimens. These studies were designed to evaluate whether the two regimens
were therapeutically equivalent, with patient and graft survival at 12
months following transplantation as the primary endpoints. The Prograf-
based immunosuppressive regimen was found to be equivalent to the
cyclosporine-based immunosuppressive regimens.
In one trial, 529 patients were enrolled at 12 clinical sites in the United
States; prior to surgery, 263 were randomized to the Prograf-based
immunosuppressive regimen and 266 to a cyclosporine-based immunosuppressive
regimen (CBIR). In 10 of the 12 sites, the same CBIR protocol was used,
while 2 sites used different control protocols. This trial excluded
patients with renal dysfunction, fulminant hepatic failure with Stage IV
encephalopathy, and cancers; pediatric patients (< 12 years old) were
allowed.
In the second trial, 545 patients were enrolled at 8 clinical sites in
Europe; prior to surgery, 270 were randomized to the Prograf-based
immunosuppressive regimen and 275 to CBIR. In this study, each center used
its local standard CBIR protocol in the active-control arm. This trial
excluded pediatric patients, but did allow enrollment of subjects with
renal dysfunction, fulminant hepatic failure in Stage IV encephalopathy,
and cancers other than primary hepatic with metastases.
One-year patient survival and graft survival in the Prograf-based treatment
groups were equivalent to those in the CBIR treatment groups in both
studies. The overall one-year patient survival (CBIR and Prograf-based
treatment groups combined) was 88% in the U.S. study and 78% in the
European study. The overall one-year graft survival (CBIR and Prograf-based
treatment groups combined) was 81% in the U.S. study and 73% in the
European study. In both studies, the median time to convert from IV to oral
Prograf dosing was 2 days.
Because of the nature of the study design, comparisons of differences in
Страницы: 1, 2, 3, 4, 5, 6, 7, 8
