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ImunosupresanSiklosporin dan takrolimusMardiyati Hasanah1111013018Kelas BSiklosporin dan Takrolimus memiliki struktur kimia yang berbeda tetapi bekerja dengan mekanisme yang sama yaitu menghambat kalsineurinDengan 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 cyclosporinCsA 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 Tacrolimusabsorbsipada 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)

distribusiVenkataramanan 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)

metabolismeada 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 hatiSeveral 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 TacrolimusTacrolimus 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 obatPemberian 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)