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)
| | | |
| |WARNING | |
| |Increased susceptibility to infection and the possible | |
| |development of lymphoma may result from immunosuppression. Only | |
| |physicians experienced in immunosuppressive therapy and | |
| |management of organ transplant patients should prescribe | |
| |Prograf. Patients receiving the drug should be managed in | |
| |facilities equipped and staffed with adequate laboratory and | |
| |supportive medical resources. The physician responsible for | |
| |maintenance therapy should have complete information requisite | |
| |for the follow-up of the patient. | |
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.
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.)
|Popula|N |Route |Parame| | | | | |
|tion | |(Dose) |ters | | | | | |
| | | |Cmax |Tmax |AUC |tЅ |Cl |V |
| | | |(ng/mL|(hr) |(ng·hr/m|(hr) |(L/hr/kg|(L/kg)|
| | | |) | |L) | |) | |
|Health|8 |IV | | |598* |34.2 |0.040 |1.91 |
|y | |(0.025 |— |— |± 125 |± 7.7 |±0.009 |±0.31 |
|Volunt| |mg/kg/4hr) | | | | | | |
|eers | | | | | | | | |
| |16 |PO |29.7 |1.6 |243** |34.8 |0.041† |1.94† |
| | |(5 mg) |±7.2 |±0.7 |±73 |±11.4 |±0.008 | |
| | | | | | | | |±0.53 |
|Kidney|26 |IV | | |294*** |18.8 |0.083 |1.41 |
| | |(0.02 |— |— |±262 |±16.7 |±0.050 |±0.66 |
|Transp| |mg/kg/12hr)| | | | | | |
|lant | | | | | | | | |
|Pts | | | | | | | | |
| | |PO |19.2 |3.0 |203*** |# |# |# |
| | |(0.2 |±10.3 | |±42 | | | |
| | |mg/kg/day) | | | | | | |
| | |PO |24.2 |1.5 |288*** |# |# |# |
| | |(0.3 |±15.8 | |±93 | | | |
|Liver |17 |IV |— |— |3300*** |11.7 |0.053 |0.85 |
|Transp| |(0.05 | | | |±3.9 |±0.017 |±0.30 |
|lant | |mg/kg/12 | | |±2130 | | | |
|Pts | |hr) | | | | | | |
| | |PO |68.5 |2.3 |519*** |# |# |# |
| | |(0.3 |±30.0 |±1.5 |±179 | | | |
† 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
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