Реферат: Такролимус
Реферат: Такролимус
БАШКИРСКИЙ ГОСУДАРСТВЕННЫЙ МЕДИЦИНСКИЙ УНИВЕРСИТЕТ
КАФЕДРА ФАРМАКОЛОГИИ №1 , С КУРСОМ КЛИНИЧЕСКОЙ ФАРМАКОЛОГИИ
Зав. кафедры: д.м.н. профессор Алехин Е.К.
Зав. курсом: д.м.н. профессор Зарудий Ф.А.
Преподаватель: к.м.н. доцент Шигаев Н.И.
РЕФЕРАТ
«Такролимус»
Выполнил: студент лечебного факультета гр.№ Л-Б
УФА-2002г.
Prograf Prescribing Information
- WARNING
- DESCRIPTION:
- CLINICAL PHARMACOLOGY:
- INDICATIONS AND USAGE:
- CONTRAINDICATIONS:
- WARNINGS:
- PRECAUTIONS:
- ADVERSE REACTIONS:
- OVERDOSAGE:
- DOSAGE AND ADMINISTRATION:
- HOW SUPPLIED:
- REFERENCE
Fujisawa
Revised: May 2002
Prograf®
tacrolimus capsules
tacrolimus injection (for intravenous infusion only)
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DESCRIPTION:
Prograf is available for oral administration as capsules (tacrolimus capsules) containing the equivalent of 0.5 mg, 1 mg or 5 mg of anhydrous tacrolimus. Inactive ingredients include lactose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. The 0.5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium dioxide and ferric oxide.
Prograf is also available as a sterile solution (tacrolimus injection) containing the equivalent of 5 mg anhydrous tacrolimus in 1 mL for administration by intravenous infusion only. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol, USP, 80.0% v/v. Prograf injection must be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.
Tacrolimus,
previously known as FK506, is the active ingredient in Prograf. Tacrolimus is a
macrolide immunosuppressant produced by Streptomyces tsukubaensis.
Chemically, tacrolimus is designated as [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,
13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-
[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14, 16-dimethoxy-4,10,12,
18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c][1,4]
oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate.
The chemical structure of tacrolimus is:
Tacrolimus has an empirical formula of C44H69NO12 ·H2O and a formula weight of 822.05. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform.
CLINICAL PHARMACOLOGY:
Mechanism of Action
Tacrolimus prolongs the survival of the host and transplanted graft in animal transplant models of liver, kidney, heart, bone marrow, small bowel and pancreas, lung and trachea, skin, cornea, and limb.
In animals, tacrolimus has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed type hypersensitivity, collagen- induced arthritis, experimental allergic encephalomyelitis, and graft versus host disease.
Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
Pharmacokinetics
Tacrolimus activity is primarily due to the parent drug. The pharmacokinetic parameters (mean±S.D.) of tacrolimus have been determined following intravenous (IV) and oral (PO) administration in healthy volunteers, kidney transplant and liver transplant patients. (See table below.)
|
Population |
N |
Route |
Parameters |
|||||
|
Cmax |
Tmax |
AUC |
t½ |
Cl |
V |
|||
|
Healthy |
8 |
IV |
|
|
598* |
34.2 |
0.040 |
1.91 |
| 16 |
PO |
29.7 |
1.6 |
243** |
34.8 |
0.041† |
1.94† |
|
|
Kidney |
26 |
IV |
|
|
294*** |
18.8 |
0.083 |
1.41 |
|
PO |
19.2 |
3.0 |
203*** |
# | # | # | ||
|
PO |
24.2 |
1.5 |
288*** |
# | # | # | ||
|
Liver |
17 |
IV |
— | — |
3300*** |
11.7 |
0.053 |
0.85 |
|
PO |
68.5 |
2.3 |
519*** |
# | # | # | ||
† Corrected for individual bioavailability * AUC0-120 ** AUC0-72 *** AUC0-inf — not applicable # not available
Due to intersubject variability in tacrolimus pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. (See DOSAGE AND ADMINISTRATION). Pharmacokinetic data indicate that whole blood concentrations rather than plasma concentrations serve as the more appropriate sampling compartment to describe tacrolimus pharmacokinetics.
Absorption
Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability of tacrolimus was 17±10% in adult kidney transplant patients (N=26), 22±6% in adult liver transplant patients (N=17), and 18±5% in healthy volunteers (N=16).
A single dose study conducted in 32 healthy volunteers established the bioequivalence of the 1 mg and 5 mg capsules. Another single dose study in 32 healthy volunteers established the bioequivalence of the 0.5 mg and 1 mg capsules. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7 and 10 mg.
In 18 kidney transplant patients, tacrolimus trough concentrations from 3 to 30 ng/mL measured at 10-12 hours post-dose (Cmin) correlated well with the AUC (correlation coefficient 0.93). In 24 liver transplant patients over a concentration range of 10 to 60 ng/mL, the correlation coefficient was 0.94.
Food Effects: The rate and extent of tacrolimus absorption were greatest under fasted conditions. The presence and composition of food decreased both the rate and extent of tacrolimus absorption when administered to 15 healthy volunteers.
The effect was most pronounced with a high-fat meal (848 kcal, 46% fat): mean AUC and C max were decreased 37% and 77%, respectively; Tmax was lengthened 5-fold. A high-carbohydrate meal (668 kcal, 85% carbohydrate) decreased mean AUC and mean C max by 28% and 65%, respectively.
In healthy volunteers (N=16), the time of the meal also affected tacrolimus bioavailability. When given immediately following the meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was 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 |
t½ |
V |
Cl |
|
Renal |
0.02 |
393±123 (t = 60hr) |
26.3±9.2 |
1.07 |
0.038 |
|
Mild Hepatic |
0.02 |
367±107 (t=72hr) |
60.6±43.8 |
3.1 |
0.042 |
|
7.7 mg |
488±320 (t = 72hr) |
66.1±44.8 |
3.7 |
0.034 |
|
|
Severe Hepatic |
0.02 |
762±204 |
198±158 |
3.9 |
0.017 |
|
0.01 |
289±117 |
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Severe Hepatic (n=5, PO)† |
8 mg PO |
658 |
119±35 |
3.1 |
0.016 |
|
5mg PO |
533±156 |
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|
4 mg PO |
