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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)

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.

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 (Dose)	Parameters
Population	N	Route (Dose)	Cmax (ng/mL)	Tmax (hr)	AUC (ng·hr/mL)	t½ (hr)	Cl (L/hr/kg)	V (L/kg)
Healthy Volunteers	8	IV (0.025 mg/kg/4hr)	—	—	598* ± 125	34.2 ± 7.7	0.040 ±0.009	1.91 ±0.31
Healthy Volunteers	16	PO (5 mg)	29.7 ±7.2	1.6 ±0.7	243** ±73	34.8 ±11.4	0.041† ±0.008	1.94† ±0.53
Kidney Transplant Pts	26	IV (0.02 mg/kg/12hr)	—	—	294*** ±262	18.8 ±16.7	0.083 ±0.050	1.41 ±0.66
		PO (0.2 mg/kg/day)	19.2 ±10.3	3.0	203*** ±42	#	#	#
		PO (0.3 mg/kg/day)	24.2 ±15.8	1.5	288*** ±93	#	#	#
Liver Transplant Pts	17	IV (0.05 mg/kg/12 hr)	—	—	3300*** ±2130	11.7 ±3.9	0.053 ±0.017	0.85 ±0.30
Liver Transplant Pts	17	PO (0.3 mg/kg/day)	68.5 ±30.0	2.3 ±1.5	519*** ±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.

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