IMMUNOSUPPRESSANTS

TAHUN AKADEMIK 2014

Tugas Ke-2
Sekolah Tinggi Ilmu Farmasi
Bhakti Pertiwi Palembang
Kelompok 9 Kelas D + Ekstensi

Arum Kinanti
Fathia Nurhasana
Puguh Suwasono
Rud Damayanti
Ambarwati

(11.01.01.154)
(11.01.01.161)
(11.01.01.169)
(12.01.03.033)
(

CYCLOSPORINE
Cyclosporine is a cyclic polypeptide with
immunosuppressant properties that is used for
the prevention of graft-versus-host disease in
hematopoietic 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)

THERAPEUTIC AND 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) assay
techniques 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)

 Newer monoclonal fluorescence polarization

(monoclonal TDx assay) and radioimmunoassays
(various) are now available that are relatively
specific for cyclosporine and produce results similar
to the HPLC assay
Since cyclosporine metabolites are excreted in the
bile, liver transplant patients immediately after
surgery can have very high cyclosporine metabolite
concentrations in the blood, serum, and plasma
because bile production has not begun yet in the
newly transplanted organ.
For patients receiving cyclosporine after a
hematopoietic 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)

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

and producing an immunologic response
against these antigens and host tissues.
Acute graft-versus-host disease usually occurs
within the first 100 days after transplantation
of donor cells, and causes epithelial tissue
damage in organs. The most common tissues
attacked are skin, gastrointestinal tract, and
liver.
To prevent acute graft-versus-host disease
from occurring in allogenic hematopoietic stem
cell transplantation patients with HLA-identical
sibling donors. (Bauer L.A, 2008:651)

 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 drug
discontinuation by about post-transplant day 180.
For allogeneic hematopoietic stem cell
transplantation patients with HLA-mismatched or
HLA-identical unrelated donors, the risk of acute
graft-versus-host disease is higher, so cyclosporine
therapy may be more prolonged for these patients.
(Bauer L.A, 2008:651)

 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.

 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, cyclosporine
therapy 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)

 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)

CLINICAL MONITORING
PARAMETERS
Hematopoietic stem cell transplantation patients
should be monitored for the signs and symptoms
associated with graft-versus-host disease.
These include a generalized maculopapular skin
rash, diarrhea, abdominal pain, ileus,
hyperbilirubinemia, and increased liver function
tests (serum transaminases and alkaline
phosphatase).
Patients with severe chronic graft-versus-host
disease may have involvement of the skin, liver,
eyes, mouth, esophagus,or other organs similar to
what might be seen with systemic autoimmune
diseases. (Bauer L.A, 2008:652)

 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)

 Chronic rejection in heart transplant patients, also

known 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 biopsies
may be taken from the transplanted tissue to confirm
the diagnosis of organ rejection
Other cyclosporine adverse drug reactions that occur
less frequently include gastrointestinal side effects
(nausea, vomiting, diarrhea), headache, hepatotoxicity,
hyperglycemia, acne, leukopenia, hyperkalemia, and
hypomagnesemia. (Bauer L.A, 2008:652)

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 tercapai
setelah 1,3 sampai 4 jam.
(Farmakologi dan Terapi, 2007:761)

 Adanya makanan berlemak sangat mengurangi

absorpsi siklosporin kapsul lunak, tapi tidak
siklosporin mikroemulsi.
Siklosporin mengalami distribusi yang luas dengan
volume distribusi 3-5 liter/kg.
Dalam darah 50-60% siklosporin terakumulasi
dalam eritrosit, dan 10-20% dalam leukosit dan
sisanya berada dalam plasma. Waktu paruh
siklosporinkurang lebih 6 jam.
Siklosporin mengalami metabolisme dalam hati
oleh 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)

 Sebagian dari metabolit masih bersifat

imunosupresif dan diduga berperan dalam
toksisitas.
Ekskresi terutama melalui empedu dan
feses, hanya sekitar 6% yang diekskresi
melalui urin.
Dalam keadaan gangguan fungsi hati
memerlukan penyesuaian dosis.
(Farmakologi dan Terapi, 2007:761)

EFFECTS OF DISEASE STATES AND CONDITIONS ON

CYCLOSPORINE PHARMACOKINETICS AND DOSING
Transplantation type does not appear to have a
substantial effect on cyclosporine pharmacokinetics.
The overall mean for all transplant groups is a
clearance 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 (16
years old).
Because the drug is primarily eliminated by hepatic
metabolism, clearance is lower (3 mL/min/kg) and
half-life prolonged (20 hours) in patients with liver
failure. (Bauer L.A, 2008:655)

 patients with transient liver dysfunction,

regardless of transplantation type, will have
decreased cyclosporine clearance and increased
half-life values
Obesity does not influence cyclosporine
pharmacokinetics, so doses should be based on
ideal body weight for these individuals.
Renal failure does not change cyclosporine
pharmacokinetics, and the drug is not significantly
removed by hemodialysis or peritoneal dialysis
(Bauer L.A, 2008:655)

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 profile
would be assumed to have a cyclosporine
clearance of 10 mL/min/kg.

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 steadystate 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 populations
and 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

 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 that
method of administration is Css = ko/Cl, or ko
= Css Cl, where ko is the infusion rate.

STEADY-STATE CONCENTRATION SELECTION

The generally accepted therapeutic ranges for
cyclosporine in blood, serum, or plasma using
various specific and nonspecific (parent drug +
metabolite) assays are given in Table 15-1.

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

TACROLIMUS
Tacrolimus (also known as FK506) is a macrolide
compound with immunosuppressant actions that is
used 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-2
and 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 with
calcineurin, 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)

THERAPEUTIC AND TOXIC

CONCENTRATIONS
For patients receiving solid organ transplants such as
kidney, 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, tacrolimus
therapy 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)

 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)

 Chronic nephrotoxicity is accompanied

by kidney tissue damage, including
interstitial fibrosis, nonspecific tubular
vacuolization, and structural changes in
arteries, arterioles, and proximal tubular
epithelium.
Dosage decreases may be necessary to limit
adverse drug effects associated with
tacrolimus therapy.
(Bauer L.A, 2008:684)

CLINICAL MONITORING
PARAMETERS
For renal transplant patients, increased serum
creatinine, 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 renal
function (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 and
symptoms 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)

 For heart transplant patients, acute rejection is

accompanied by low-grade fever, malaise, heart
failure (presence of S3 heart sound), or atrial
arrhythmia.
Typical adverse effects of tacrolimus treatment
include neurotoxicity, nephrotoxicity,
hypertension, hyperkalemia, hypomagnesemia,
glucose intolerance, gastrointestinal upset,
hepatotoxicity, pruritus, alopecia, and leukocytosis.
Other tacrolimus adverse drug reactions that occur
less frequently include hyperlipidemia and
thrombocytopenia.
(Bauer L.A, 2008:685)

BASIC CLINICAL PHARMACOKINETIC

PARAMETERS
Tacrolimus is almost completely eliminated by
hepatic 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 significant
immunosuppressive effects in humans. Most of the
metabolites are eliminated in the bile. Less than 1%
of a tacrolimus dose is recovered as unchanged drug
in the urine
Tacrolimus has low water solubility, and its
gastrointestinal absorption can be influenced by
many variables (Bauer L.A, 2008:685)

 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 with
grapefruit juice since this vehicle inhibits
CYP3A4 and/or P-glycoprotein contained in the
gastrointestinal tract and markedly increases
bioavailability
(Bauer L.A, 2008:686)

 Tacrolimus is a low hepatic extraction ratio drug.

Because of this, its hepatic clearance is influenced
by unbound fraction in the blood (fB) and intrinsic
clearance (Clint). Tacrolimus binds primarily to
erythrocytes, 1-acid glycoprotein, and albumin.
Tacrolimus capsules are available in 0.5, 1, and 5
mg strengths. Tacrolimus injection for intravenous
administration is available at a concentration of 5
mg/mL.
The initial dose of tacrolimus varies greatly among
various transplant centers with a range of 0.10.3
mg/kg/d for orally administered drug and 0.030.1
mg/kg/d for intravenously administered drug.
(Bauer L.A, 2008:686)

 For patients with liver dysfunction, these doses

may be reduced by 2550%. Tacrolimus therapy
may be started before the transplantation
procedure.
Recommended initial oral doses of tacrolimus
are 0.2 mg/kg/d for adult kidney transplant
patients, 0.100.15 mg/kg/d for adult liver
transplant patients, 0.150.2 mg/kg/d for
pediatric 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)

EFFECTS OF DISEASE STATES AND CONDITIONS ON

TACROLIMUS
PHARMACOKINETICS AND DOSING

The overall mean for all transplant groups is a clearance

of 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 (16
years 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) in
adult 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)

INITIAL DOSAGE DETERMINATION

METHODS
Pharmacokinetic Dosing Method
CLEARANCE ESTIMATE
Tacrolimus is almost completely metabolized
by 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 the
same profile would be assumed to have a
tacrolimus clearance of 0.138 L/h/kg.
(Bauer L.A, 2008:689)

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 steadystate 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 of
tacrolimus in milligrams, Cl is tacrolimus clearance in
liters per hour, and is the dosage interval in hours
(Bauer, L.A, 2008:689)

STEADY-STATE CONCENTRATION
SELECTION
The generally accepted therapeutic range
for tacrolimus in the blood is 520 ng/mL.
(Bauer L.A, 2008:689)

Referensi
Bauer, L.A. 2008. Applied Clinical
Pharmacokinetics. Second edition. New York:
Mc-Graw-Hill.
Farmakologi dan Terapi. 2007. Jakarta: Balai
Penerbit FK UI