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.)

| | | |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 |

| |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 |

|Pts | | | | | | | | |

| | |PO |19.2 |3.0 |203*** |# |# |# |

| | |(0.2 |±10.3 | |±42 | | | |

| | |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 |

|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

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 |tЅ |V |Cl |

|Patients) | |) | |) | |

|Renal |0.02 |393±123 |26.3±9.2 |1.07 |0.038 |

|Impairment |mg/kg/4h|(t = | | |±0.014 |

|(n=12) |r |60hr) | |±0.20| |

| |IV | | | | |

|Mild Hepatic |0.02 |367±107 |60.6±43.8 |3.1 |0.042 |

|Impairment |mg/kg/4h|(t=72hr) |Range: 27.8 - |±1.6 |±0.02 |

|(n=6) |r | |141 | | |

| |IV | | | | |

| |7.7 mg |488±320 |66.1±44.8 |3.7 |0.034 |

| |PO |(t = |Range: 29.5 - |±4.7*|±0.019* |

| | |72hr) |138 | | |

|Severe Hepatic |0.02 |762±204 |198±158 |3.9 |0.017 |

|Impairment |mg/kg/4h|(t=120hr)|Range: 81-436 |±1.0 |±0.013 |

|(n=6, IV) |r | | | | |

| |IV (n=2)| | | | |

| | | | | | |

| |0.01 |289±117 | | | |

| |mg/kg/8h|(t=144hr)| | | |

| |r | | | | |

| |IV (n=4)| | | | |

| | | | | | |

|Severe Hepatic |8 mg PO |658 |119±35 |3.1 |0.016 |

|Impairment |(n=1) |(t=120hr)|Range: 85-178 |±3.4*|±0.011* |

|(n=5, PO)† | | | | | |

| |5mg PO |533±156 | | | |

| |(n=4) |(t=144hr)| | | |

| |(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.

Because of the nature of the study design, comparisons of differences in

secondary endpoints, such as incidence of acute rejection, refractory

rejection or use of OKT3 for steroid-resistant rejection, could not be

reliably made.

Kidney Transplantation

Prograf-based immunosuppression following kidney transplantation was

assessed in a Phase III randomized, multicenter, non-blinded, prospective

study. There were 412 kidney transplant patients enrolled at 19 clinical

sites in the United States. Study therapy was initiated when renal function

was stable as indicated by a serum creatinine < 4 mg/dL (median of 4 days

after transplantation, range 1 to 14 days). Patients less than 6 years of

age were excluded.

There were 205 patients randomized to Prograf-based immunosuppression and

207 patients were randomized to cyclosporine-based immunosuppression. All

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