Imunosupresan

Siklosporin dan takrolimus

Mardiyati Hasanah
1111013018
Kelas B
Siklosporin dan Takrolimus memiliki struktur
kimia yang berbeda tetapi bekerja dengan
mekanisme yang sama yaitu menghambat
kalsineurin
Dengan terhambatnya kalsineurin maka akan
menghambat transkripsi gen pada limfosit T
(CD4) sehingga tidak dapat membentuk sel sel
imun yang aktif. (Farmakologi dan terapi FKUI 2007)
Siklosporin
Tersedia dalam sediaan IV yang terdapat dalam
bentuk larutan ethanol-polyoxyethylated-castor
oil dengan kadar 50 mg/mL. sediaan oral berupa
kapsul lunak 25-100 mg dan larutan 100 mg/mL.
Absorbsi oral lambat dan tidak lengkap, dengan
bioavailabilitas 20-50%. Sediaan modifikasi dalam
bentuk mikroemulsi menghasilkan absorbsi yg
lebih baik
(Farmakologi dan terapi FKUI 2007)
Sediaan IV dan sediaan oral bersifat tidak
bioekuivalen, sehingga penggantian dari sediaan
IV ke oral harus dilakukan dengan perhitungan
yang cermat.
Pada pemberian peroral kadar puncak tercapai
setelah 1,3-4 jam. Adanya makanan berlemak
sangat mengurangi absorbsi siklosporin kapsul
lunak, tapi tidak untuk sediaan mikroemulsi.
Memiliki VD 3-5 liter/Kg. dalam darah 50-60%
siklosporin terakumulasi dalam eritrosit dan 10-
20% dalam leukosit, sisanya dalam plasma.
Waktu paruh kurang lebih 6 jam. (Farmakologi
dan terapi FKUI 2007)
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.
Sebagian dari metabolit mash 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, diperlukan
penyesuaian dosis.
(Farmakologi dan terapi FKUI 2007)
Chemistry cyclosporin
CsA is a neutral, hydrophobic, cyclic polypeptide
(11 amino acids) which is classified as an
immunosuppressive antibiotic (others being
rapamycin, tacrolimus and dapsone). It is a
powdery crystalline compound which is highly
lipophilic, meaning that the drug dissolves in
liquid fats and organic solvents but not in water.
For this reason it has to be dissolved in oil
(usually castor or olive oil) for clinical use.
(Calonge, Margarita.Cyclosporine.American Uveit society)
Monitoring Siklosporin (CSA)
The most worrisome side effects of CsA include
high blood pressure and a decrease in kidney
function. Both side effects are typically reversible
by reducing the dosage or discontinuing the drug.
It is therefore important that blood pressure and
blood chemistry (especially kidney function) are
routinely monitored.
(Calonge, Margarita.Cyclosporine.American Uveit
society)

A decrease in the white blood cell count does not
usually occur. More common side effects include
nausea and vomiting, tingling in the arms and
legs, increased sensitivity to temperature
changes, hand tremor, hirsutism (excess growth
of hair on the face, chest, and back) and gingival
hyperplasia (enlargment of the gums, which can
be minimized by good oral hygiene). These side
effects are typically reversible. All patients on
immunosuppressive therapy are at increased risk
for infections, especially atypical or
opportunistic infections.
(Calonge, Margarita.Cyclosporine.American Uveit
society)

The extent of this risk is generally slight, but
increases if other immunosuppressive
medications are being taken in conjunction
with cyclosporine. Malignancies possibly
secondary to cyclosporine therapy have been
described but are extremely rare.
(Calonge, Margarita.Cyclosporine.American
Uveit society)

Takrolimus
Tacrolimus is a membered macrolide lactone
which is isolated from the fermentation broth of
Streptomyces tsukubaesis. Additionally,
tacrolimus like cyclosporin is an
immunosuppressive agent belonging to the
calcineurin inhibitor group that has emerged as a
valuable therapeutic alternative to cyclosporine
following solid organ transplantation. It is highly
effective at preventing rejection in heart, small
bowel, pancreas, bone marrow, lung, liver, and
kidney recipients and for the therapy of
autoimmune diseases.
(Den Buijsch, Robert. Pharmacokinetics and pharmacogenomics of
tacrolimus: a review)
Dapat diberikan secara IV dan peroral. Setelah
pemberian IV selama 2-4 jam, kadar takrolimus
mula-mula akan turun, selanjutnya takrolimus
akan menunjukkan waktu paruh yang cukup
panjang, yaitu 11,7 jam pada pasien transplantasi
hati dan 21,2 jam pada orang sehat. Data ini
menunjukkan adanya kinetika model dua
kompartemen. Pada pemberian oral,
bioavailibilitas bervariasi dari 6-56%.
(Farmakologi dan terapi FKUI 2007)
Takrolimus sebagian besar menalami
metabolisme di hati oleh sitokrom p-450 dan
hanya 1% yang diekskresi utuh dalam urin.
Dosis IV untuk dewasa adalah 25-50 mg/KgBB
per hari dan pada anak 50-100 mg/KgBB per
hari. Dosis oral berkisar antara 150-200
mg/KgBB per hari dan pada anak 200-300
mg/KgBB per hari. (Farmakologi dan terapi
FKUI 2007)
ADME Tacrolimus
absorbsi
pada administrasi oral memiliki laju absorbsi yg
bervariasi yang sehingga rata-rata absorbsinnya
biasanya 25%, tetapi dapat berkisar antara 5-
93%. umumnya dosis oral harus lebih tinggi 3-4
kali dosis IV untuk mencapai efek obat yg sama.
selain dimetabolisme oleh enzim sitokrom P450,
P-glikoprotein juga menyebabkan turunnya kadar
tacrolimus pada intrasel, karena P-glikoprotein
memompa kembali tacrolimus yg telah diabsorbsi
keluar ke lumen intestinal.
(Den Buijsch, Robert. Pharmacokinetics and
pharmacogenomics of tacrolimus: a review)


distribusi
Venkataramanan et al melaporkan bahwa jumlah
maksimum tacrolimus yg berikatan dengan sel
darah merah adalah 418 258 g/l. Difusi
tacrolimus dari erythocytes lambat dibandingkan
dengan waktu transit darah melalui organ , tetapi
tacrolimus yang mudah dilepaskan dari
erythrocytes. tacrolimus dapat melewati plasenta
dan kelenjar susu.
(Den Buijsch, Robert. Pharmacokinetics and
pharmacogenomics of tacrolimus: a review)


metabolisme
ada 2 step reaksi metabolisme dari tacrolimus :
oksidasi oleh enzim sitokrom P450 yang
menidakstabilkan cincin makrolida dan rearrangement
dari struktur tacrolimus tsb (Schuler et al).

eliminasi:
metabolit dari tacrolimus lebih dari 95% dieliminasi
melalui rute empedu. eksresi melalui urin berkisar
2,4%.
(Den Buijsch, Robert. Pharmacokinetics and
pharmacogenomics of tacrolimus: a review)

Tacrolimus pada gangguan fungsi hati
Several studies already reported that a poor liver function
can decrease tacrolimus clearance up to 67% and increase
the elimination half-life with a threefold. Cold ischaemia
time and reperfusion injury to a transplanted liver may also
alter the clearance of tacrolimus. However, tacrolimus
clearance has been reported to be similar between healthy
volunteers and patients with mild hepatic impairment.
Transplant patient who are hepatitis C positive require a
significantly lower mean dosage of tacrolimus than hepatic
C negative patients to obtain the same trough
concentrations. Horina et al. suggested that replication of
the hepatitis virus in liver cells alters the cytochrome P450
system which results in reduced tacrolimus metabolism.
(Den Buijsch, Robert. Pharmacokinetics and
pharmacogenomics of tacrolimus: a review)

TDM Tacrolimus

Tacrolimus has a narrow therapeutic index and highly
variable pharmacokinetic characteristics
Based on the half-life of tacrolimus which is approximately
ten hours, it is necessary to wait at least 36 hours (3.3 half-
lives) to reach a steady state tacrolimus concentration after
initiation of therapy or after a change in the administration
regime of tacrolimus. Ideally, after starting the infusion,
blood concentrations should be monitored on day 2 or 3
on average 3 to 7 times weekly during the first few weeks
after transplantation, and less frequently thereafter. Special
circumstances such as changes in liver function, presence
of adverse effects or use of drugs that may alter tacrolimus
kinetics may warrant more frequent monitoring.
(Den Buijsch, Robert. Pharmacokinetics and
pharmacogenomics of tacrolimus: a review)


Interaksi obat
Pemberian dengan fenobarbital, fenitoin,
trimetoprim-sulfametoksazol dan rfampisin akan
memmpercepat eliminasi dan menurunkan kadar
sikrosporin yang dapat berakibat penolakan
transplantasi. Sebagian besar terjadi karena
terjadi induksi enzim sitokrom P450.
Pemberian dengan amfotericin B, eritromisin,
kotokonazol akan menurunkan klirens siklosporin
sehingga beesiko toksisitas. (Farmakologi dan
terapi FKUI 2007)
Comparison between pharmacokinetics of
oral cyclosporine(CYA) and
tacrolimus(TAC)
the Cp (Peak concentration) of cyclosporine was
comparatively higher than that of tacrolimus and, on
the other hand, the Ct (Plasma Concentration) of
cyclosporine was lower than tacrolimus, which
illustrated a blood concentration time curve with a
sharp peak.
On the other hand, the pharmacokinetics of TAC
showed that the Cp of TAC was lower and the Ct was
higher, which illustrated a gently hunched blood
concentration time curve, which was similar to the
curve for continuous intravenous infusion.
(Takeuchi, Hironori. Optimal Pharmacokinetics of Cyclosporine and Tacrolimus
Based Relationship Among AUC, Trough and Peak Concentration)