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(r) 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 Cmax (ng/mL) Tmax (hr) AUC (ng·hr/mL) t1/2 (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 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 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. ............