Реферат: Такролимус
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 (No. of Patients) | Dose | AUC 0-t (ng·hr/mL) | t½ (hr) | V (L/kg) | Cl (L/hr/kg) |
| Renal Impairment (n=12) | 0.02 mg/kg/4hr IV | 393±123 (t = 60hr) | 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=72hr) | 60.6±43.8 Range: 27.8 - 141 | 3.1 ±1.6 | 0.042 ±0.02 |
| 7.7 mg PO | 488±320 (t = 72hr) | 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=144hr) | ||||
Severe Hepatic (n=5, PO)† | 8 mg PO (n=1) | 658 (t=120hr) | 119±35 Range: 85-178 | 3.1 ±3.4* | 0.016 ±0.011* |
| 5mg PO (n=4) | 533±156 (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.