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IMMUNOSUPPRESSANTS

TAHUN AKADEMIK 2 14


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Tugas Ke-2

Sekolah Tinggi Ilmu Farmasi

Bhakti Pertiwi Palembang

Kelompok 9 Kelas D Ekstensi

Arum Kinanti (11.01.01.154)

Fathia Nurhasana (11.01.01.161) Puguh Suwasono (11.01.01.169)

Rud Damayanti (12.01.03.033)

Ambarwati (


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CYCLOSPORINE

Cyclosporine is a cyclic polypeptide with

immunosuppressant properties that is used for

the prevention of graft-versus-host disease inhematopoietic stem cell transplantation

patients, for the prevention of graft rejection in

solid organ transplant patients, and for the

treatment of psoriasis, rheumatoid arthritis and

a variety of other autoimmune diseases.

(Bauer L.A. 2008:649)


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THERAPEUTICAND TOXIC

CONCENTRATIONS

Because cyclosporine is bound to red blood cells,blood concentrations are higher than simultaneously

measured serum or plasma concentrations.

High pressure liquid chromatography (HPLC) assaytechniques are specific for cyclosporine

measurement in blood, serum, or plasma.

However, older immunoassays conducted via

fluorescence polarization (polyclonal TDx assay, Abbott Diagnostics) or radioimmunoassay

(polyclonal RIA, various manufacturers) are

nonspecific and measure both cyclosporine and its

metabolites. (Bauer L.A, 2008:649)


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Newer monoclonal fluorescence polarization(monoclonal TDx assay) and radioimmunoassays

(various) are now available that are relatively

specific for cyclosporine and produce results similarto the HPLC assay

Since cyclosporine metabolites are excreted in thebile, liver transplant patients immediately after

surgery can have very high cyclosporine metaboliteconcentrations in the blood, serum, and plasma

because bile production has not begun yet in the

newly transplanted organ.

For patients receiving cyclosporine after ahematopoietic stem cell transplantation, the goal of

therapy is to prevent graft-versus-host disease while

avoiding adverse effects of immunosuppressant

therapy. (Bauer L.A, 2008:650)


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Graft-versus-host disease is a result of donor T-lymphocytes detecting antigens on host tissues

and producing an immunologic response

against these antigens and host tissues.

Acute graft-versus-host disease usually occurswithin the first 100 days after transplantation

of donor cells, and causes epithelial tissuedamage in organs. The most common tissues

attacked are skin, gastrointestinal tract, and

liver.

To prevent acute graft-versus-host diseasefrom occurring in allogenic hematopoietic stem

cell transplantation patients with HLA-identical

sibling donors. (Bauer L.A, 2008:651)


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Methotrexate and/or glucocorticoids are usually

also given in conjunction with cyclosporine

treatment to hematopoietic stem cell

transplantation patients. If prophylaxis of acute

graft-versus-host disease is successful,

cyclosporine doses start to be tapered on about

post-transplant day 50, with the goal of drugdiscontinuation by about post-transplant day 180.

For allogeneic hematopoietic stem cell

transplantation patients with HLA-mismatched or

HLA-identical unrelated donors, the risk of acutegraft-versus-host disease is higher, so cyclosporine

therapy may be more prolonged for these patients.

(Bauer L.A, 2008:651)


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For patients receiving solid organ transplants such as

kidney, liver, heart, lung, or heart-lung transplantation, the

goal of cyclosporine therapy is to prevent acute or chronic

rejection of the transplanted organ while minimizing drug

side effects.

recipients immune system detects foreign antigens on the

donor organ which produces an immunologic response

against the graft

This leads to inflammatory and cytotoxic effects directed

against the transplanted tissue, and produces the risk of

organ tissue damage and failure. rejected kidney transplant, it is possible to remove the

graft and place the patient on a form of dialysis to sustain

their life. However, for other solid organ transplantation

patients, graft rejection can result in death.


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Because cyclosporine can cause nephrotoxicity, many

centers delay cyclosporine therapy in renal transplant

patients for a few days or until the kidney begins

functioning to avoid untoward effects on the newly

transplanted organ

cyclosporine concentrations in renal transplant patients

are generally lower to avoid toxicity in the new renal

graft than for other transplant patients (typically 100200

ng/mL versus 150300 ng/mL using whole blood with a

specific, high pressure liquid chromatograph assay)

For other solid organ transplant patients, cyclosporinetherapy may be started several hours before surgery or,

for patients with poor kidney function, held until after

transplantation to avoid nephrotoxicity.

(Bauer L.A 2008:651)


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Hypertension, nephrotoxicity, hyperlipidemia,

tremor, hirsutism, and gingival hyperplasia are all

typical adverse effects of cyclosporine treatment

Renal damage in this situation is thought to result

from renal vasoconstriction which results in

increased renal vascular resistance, decreased renal

blood flow, and reduced glomerular filtration rate Cyclosporine dosage decreases may be necessary

to decrease tremor associated with drug therapy

while hirsutism is usually addressed using patient

counseling.

Gingival hyperplasia can be minimized through the

use of appropriate and regular dental hygiene and

care. (Bauer L.A, 2008:651-652)


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CLINIC L MONITORING

P R METERS

Hematopoietic stem cell transplantation patientsshould be monitored for the signs and symptoms

associated with graft-versus-host disease.

These include a generalized maculopapular skinrash, diarrhea, abdominal pain, ileus,

hyperbilirubinemia, and increased liver function

tests (serum transaminases and alkaline

phosphatase).

Patients with severe chronic graft-versus-hostdisease may have involvement of the skin, liver,

eyes, mouth, esophagus,or other organs similar to

what might be seen with systemic autoimmunediseases. (Bauer L.A, 2008:652)


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For renal transplant patients, increased serum creatinine,

azotemia, hypertension, edema, weight gain secondary to

fluid retention, graft tenderness, fever, and malaise may

result from an acute rejection episode. Hypertension,

proteinuria, a continuous decline in renal function (increases

in serum creatinine and blood urea nitrogen levels), and

uremia.

For hepatic transplant patients, acute rejection signs and

symptoms include fever, lethargy, graft tenderness,

increased white blood cell count, change in bile color or

amount, hyperbilirubinemia, and increased liver function

tests.

For heart transplant patients, acute rejection is accompanied

by low-grade fever, malaise, heart failure (presence of S3

heart sound), or atrial arrhythmia. (Bauer L.A, 2008:652)


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Chronic rejection in heart transplant patients, alsoknown as cardiac allograft vasculopathy which is

characterized by accelerated coronary artery

atherosclerosis, may include the following symptoms:

arrhythmias, decreased left ventricular function, heart

failure, myocardial infarction, and sudden cardiac

death.

For all solid organ transplant patients, tissue biopsiesmay be taken from the transplanted tissue to confirm

the diagnosis of organ rejection

Other cyclosporine adverse drug reactions that occurless frequently include gastrointestinal side effects(nausea, vomiting, diarrhea), headache, hepatotoxicity,

hyperglycemia, acne, leukopenia, hyperkalemia, and

hypomagnesemia. (Bauer L.A, 2008:652)


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Farmakokinetik Cyclosporine

Absorpsi siklosporin lambat dan tidak lengkap,dengan bioavailabilitas 20-50%. Sediaan

modifikasi dengan mikroemulsi menghasilkan

absorpsi yang lebih baik. Sediian IV dan sediaan oral bersifat tidak

bioekuivalen, sehingga penggantian dari sediaan

IV ke sediaan oral harus dilakukan dengan

perhitungan yang cermat

Pada pemberian per oral, kadar puncak tercapaisetelah 1,3 sampai 4 jam.

(Farmakologi dan Terapi, 2007:761)


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Adanya makanan berlemak sangat mengurangiabsorpsi siklosporin kapsul lunak, tapi tidak

siklosporin mikroemulsi. Siklosporin mengalami distribusi yang luas dengan

volume distribusi 3-5 liter/kg.

Dalam darah 50-60% siklosporin terakumulasidalam eritrosit, dan 10-20% dalam leukosit dansisanya berada dalam plasma. Waktu paruh

siklosporinkurang lebih 6 jam.

Siklosporin mengalami metabolisme dalam hatioleh sitokrom-P450 3A (CYP3A) menjadi lebih dari

30 macam metabolit. Hanya sekitar 0,1% yang

diekskresi dalam bentuk utuh ke urin.

(Farmakologi dan Terapi, 2007:761)


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Sebagian dari metabolit masih bersifat

imunosupresif dan diduga berperan dalamtoksisitas.

Ekskresi terutama melalui empedu dan

feses, hanya sekitar 6% yang diekskresimelalui urin.

Dalam keadaan gangguan fungsi hati

memerlukan penyesuaian dosis. (Farmakologi dan Terapi, 2007:761)


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EFFECTS OF DISEASE STATES AND CONDITIONS ON

CYCLOSPORINE PHARMACOKINETICS AND DOSING

Transplantation type does not appear to have asubstantial effect on cyclosporine pharmacokinetics.

The overall mean for all transplant groups is aclearance of 6 mL/min/kg, a volume of distribution

equal to 5 L/kg, and a half-life of 10 hours for adults.

Average clearance is higher (10 mL/min/kg) and

mean half-life is shorter (6 hours) in children (16years old).

Because the drug is primarily eliminated by hepaticmetabolism, clearance is lower (3 mL/min/kg) and

half-life prolonged (20 hours) in patients with liver

failure. (Bauer L.A, 2008:655)


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patients with transient liver dysfunction,

regardless of transplantation type, will have

decreased cyclosporine clearance and increasedhalf-life values

Obesity does not influence cyclosporinepharmacokinetics, so doses should be based on

ideal body weight for these individuals.

Renal failure does not change cyclosporinepharmacokinetics, and the drug is not significantly

removed by hemodialysis or peritoneal dialysis

(Bauer L.A, 2008:655)

OS G


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INITIAL DOSAGE

DETERMINATION METHODS

Pharmacokinetic Dosing Method

CLEARANCE ESTIMATE

Cyclosporine is almost completely metabolized

by the liver. adult transplant patient with normal

liver function would be assigned a cyclosporine

clearance rate equal to 6 mL/min/kg, while a

pediatric transplant patient with the same profilewould be assumed to have a cyclosporine

clearance of 10 mL/min/kg.


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SELECTION OF APPROPRIATE PHARMACOKINETIC

MODEL AND EQUATIONS

When given by intravenous infusion or orally,cyclosporine follows a two-compartment modeL

equation that calculates the average cyclosporine steady-

state serum concentration (Css in ng/mL = g/L)

maintenance dose computation: Css = [F(D/)] / Cl or D

= (Css Cl ) / F

where F is the bioavailability fraction for the oral dosage

form (F averages 0.3 or 30% for most patient populationsand oral dosage forms), D is the dose of cyclosporine in

milligrams, Cl is cyclosporine clearance in liters per

hour, and is the dosage interval in hours


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If the drug is to be given intravenously as

intermittent infusions, the equivalent equation

for that route of administration is Css = (D/) /

Cl or D = Css Cl

If the drug is to be given as a continuous

intravenous infusion, the equation for thatmethod of administration is Css = ko/Cl, or ko

= Css Cl, where ko is the infusion rate.


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STEADY-STATE CONCENTRATION SELECTION

The generally accepted therapeutic ranges for

cyclosporine in blood, serum, or plasma usingvarious specific and nonspecific (parent drug +

metabolite) assays are given in Table 15-1.

(Bauer L.A, 2008:650&657)


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TACROLIMUS Tacrolimus (also known as FK506) is a macrolide

compound with immunosuppressant actions that isused for the prevention of graft rejection in solid organ

transplant patients.

The immunomodulating effects of tacrolimus result

from its ability to block the production of intraleukin-2and other cytokines produced by T-lymphocytes.3

Tacrolimus binds to FK-binding protein (FKPB), an

intracellular cytoplasmic protein found in T-cells.

The tacrolimus-FKPB complex interacts withcalcineurin, inhibits the catalytic activity of calcineurin,

and blocks the production of intermediaries involved

with the expression of genes regulating the production

of cytokines. (Bauer L.A, 2008:682)


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THER PEUTIC ND TOXIC

CONCENTR TIONS

For patients receiving solid organ transplants such askidney, liver, heart, lung, or heartlung transplantation, the

goal of tacrolimus therapy is to prevent acute or chronic

rejection of the transplanted organ while minimizing drug

side effects. However, for other solid organ transplantation patients,

graft rejection can result in death. Because tacrolimus can

cause nephrotoxicity,

For other solid organ transplant patients, tacrolimustherapy may be started several hours before surgery.

During the immediate postoperative phase, intravenous

tacrolimus may be given to these patients.

(Bauer L.A, 2008: 683)


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Neurotoxicity (coma, delirium, psychosis,encephalopathy, seizures, tremor, confusion,

headaches, paresthesias, insomnia, nightmares,photophobia, anxiety), nephrotoxicity, hypertension,

electrolyte imbalances (hyperkalemia,

hypomagnesemia), glucose intolerance, gastrointestinal

upset (diarrhea, nausea, vomiting, anorexia),

hepatotoxicity, pruritus, alopecia, and leukocytosis are

all typical adverse effects of tacrolimus treatment.

Nephrotoxicity is similar to that seen with cyclosporine,

and is separated into acute and chronic varieties. Acute nephrotoxicity is concentration or dose

dependent and reverses with a dosage decrease

(Bauer L.A, 2008:684)


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Chronic nephrotoxicity is accompanied

by kidney tissue damage, includinginterstitial fibrosis, nonspecific tubular

vacuolization, and structural changes in

arteries, arterioles, and proximal tubularepithelium.

Dosage decreases may be necessary to limit

adverse drug effects associated withtacrolimus therapy.

(Bauer L.A, 2008:684)


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CLINIC L MONITORING

P R METERS

For renal transplant patients, increased serumcreatinine, azotemia, hypertension, edema, weight gain

secondary to fluid retention, graft tenderness, fever, and

malaise may be caused by an acute rejection episode.

Hypertension, proteinuria, a continuous decline in renalfunction (increases in serum creatinine and blood urea

nitrogen levels), and uremia are indicative of chronic

rejection in renal transplant patients.

Forhepatic transplant patients, acute rejection signs andsymptoms include fever, lethargy, graft tenderness,

increased white blood cell count, change in bile color or

amount, hyperbilirubinemia, and increased liver function

tests. (Bauer L.A, 2008:684)


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For heart transplant patients, acute rejection isaccompanied by low-grade fever, malaise, heart

failure (presence of S3 heart sound), or atrialarrhythmia.

Typical adverse effects of tacrolimus treatmentinclude neurotoxicity, nephrotoxicity,

hypertension, hyperkalemia, hypomagnesemia,glucose intolerance, gastrointestinal upset,

hepatotoxicity, pruritus, alopecia, and leukocytosis.

Other tacrolimus adverse drug reactions that occurless frequently include hyperlipidemia and

thrombocytopenia.

(Bauer L.A, 2008:685)


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B SIC CLINIC L PH RM COKINETIC

P R METERS

Tacrolimus is almost completely eliminated byhepatic metabolism (>99%). Hepatic metabolism is

mainly via the CYP3A4 enzyme system, and the drug

is a substrate for P-glycoprotein

None of these metabolites appear to have significantimmunosuppressive effects in humans. Most of the

metabolites are eliminated in the bile. Less than 1%

of a tacrolimus dose is recovered as unchanged drugin the urine

Tacrolimus has low water solubility, and itsgastrointestinal absorption can be influenced by

many variables (Bauer L.A, 2008:685)


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While the average oral bioavailability is 25%,there is a large amount of variation in this

parameter among patients (489%) When given with meals, especially with high fat

content food, oral bioavailability of tacrolimus

decreases.

Oral tacrolimus should not be taken withgrapefruit juice since this vehicle inhibits

CYP3A4 and/or P-glycoprotein contained in the

gastrointestinal tract and markedly increasesbioavailability

(Bauer L.A, 2008:686)


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Tacrolimus is a low hepatic extraction ratio drug.Because of this, its hepatic clearance is influenced

by unbound fraction in the blood (fB) and intrinsicclearance (Clint). Tacrolimus binds primarily toerythrocytes, 1-acid glycoprotein, and albumin.

Tacrolimus capsules are available in 0.5, 1, and 5

mg strengths. Tacrolimus injection for intravenousadministration is available at a concentration of 5

mg/mL.

The initial dose of tacrolimus varies greatly amongvarious transplant centers with a range of 0.10.3mg/kg/d for orally administered drug and 0.030.1mg/kg/d for intravenously administered drug.

(Bauer L.A, 2008:686)


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For patients with liver dysfunction, these dosesmay be reduced by 2550%. Tacrolimus therapy

may be started before the transplantationprocedure.

Recommended initial oral doses of tacrolimusare 0.2 mg/kg/d for adult kidney transplant

patients, 0.100.15 mg/kg/d for adult livertransplant patients, 0.150.2 mg/kg/d forpediatric hepatic transplant recipients, and 0.075

mg/kg/d for adult heart transplant patients. Oral tacrolimus is usually given in two divided

daily doses given every 12 hours

(Bauer L.A, 2008:687)


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EFFECTS OF DISE SE ST TES ND CONDITIONS ON

T CROLIMUS

PH RM COKINETICS ND DOSING

The overall mean for all transplant groups is a clearanceof 0.06 L/h/kg, a volume of distribution equal to 1 L/kg,

and a half-life of 12 hours for adults. In children (16years old), average clearance and volume of distribution

are higher (0.138 L/h/kg and 2.6 L/kg, respectively) but

the mean half-life is about the same as adults (12 hours).

Because the drug is primarily eliminated by hepatic

metabolism, average clearance is lower (0.04 L/h/kg) inadult patients with liver dysfunction. Also, mean volume

of distribution is larger (3 L/kg) and half-life prolonged

and variable (mean = 60 hours, range 28141 h) in this

patient population. (Bauer L.A, 2008:687)


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INITI L DOS GE DETERMIN TION

METHODS

Pharmacokinetic Dosing Method

CLEARANCE ESTIMATE

Tacrolimus is almost completely metabolizedby the liver. an adult transplant patient with

normal liver function would be assigned a

tacrolimus clearance rate equal to 0.06 L/h/kg,

while a pediatric transplant patient with thesame profile would be assumed to have a

tacrolimus clearance of 0.138 L/h/kg.

(Bauer L.A, 2008:689)


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SELECTION OF APPROPRIATE PHARMACOKINETIC

MODEL AND EQUATIONS

When given by intravenous infusion or orally,tacrolimus follows a two-compartment model.

equation that calculates the average tacrolimus steady-

state concentration (Css in ng/mL = g/L)

maintenance dose computation: Css = [F(D/)] / Cl or

D = (Css Cl ) / F, where F is the bioavailability

fraction for the oral dosage form (F averages 0.25 or

25% for most patient populations), D is the dose oftacrolimus in milligrams, Cl is tacrolimus clearance in

liters per hour, and is the dosage interval in hours

(Bauer, L.A, 2008:689)


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STEADY-STATE CONCENTRATION

SELECTION

The generally accepted therapeutic rangefor tacrolimus in the blood is 520 ng/mL.

(Bauer L.A, 2008:689)


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Referensi

Bauer, L.A. 2008.Applied Clinical

Pharmacokinetics. Second edition. New York:

Mc-Graw-Hill.

Farmakologi dan Terapi. 2007. Jakarta: Balai

Penerbit FK UI


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