**6.15. Mechanism of action**

curiously do not demonstrate major differences in the GI side effect profile of MMF and enteric

Another major side effect of these preparations is bone marrow suppression mainly manifest‐ ing with leucopenia. Typically the dose of MMF is reduced based on the severity of leucopenia. There appears to be a correlation between the incidence of leucopenia and drug exposure. [31]

Azathioprine (Imuran) has been in use in transplantation for more than three decades. With introduction of CNIs and MMF, many centers have moved away from using azathioprine as a first line maintenance agent. SRTR reports from 2009 demonstrate that only 0.6% of the kidney transplant recipients were on Azathioprine. It is commonly used now primarily in patients who are intolerant to MMF. Usual daily dose administered is 2-3 mg/kg once daily.

Azathioprine is an antimetabolite a derivative of 6-mercaptopurine. It gets incorporated into cellular deoxyribonucleic acid (DNA). Once incorporated into DNA it interferes with tran‐ scription, purine and ribonucleic acid (RNA) synthesis which are important for T cell activa‐ tion. Azathioprine is metabolized by xanthine oxidase inhibitor to 6–thiouric acid. Hence allopurinol which is a xanthine oxidase inhibitor should be used with great caution with azathioprine as it can lead to significant toxicity. Typically the dose of azathioprine is reduced

The single most severe toxicity of azathioprine is related to suppression of bone marrow. Patients can develop profound leucopenia and thrombocytopenia. It is recommended to monitor white count and platelet count carefully every 2 weeks at initiation. The dose of the drug will need to be decreased if leucopenia occurs and severe leucopenia might necessitate discontinuation of the drug. Cholestasis, hepatic veno occlusive disease, hepatitis and rare

Sirolimus (Rapamycin) was introduced to transplantation in the late 1990s. It has antitumor, antiproliferative and immunosuppressive actions. Sirolimus plays a key role in immunosup‐ pression especially as an alternative to CNIs to minimize long term CNI induced nephrotox‐ icity. SRTR database reported that the use of sirolimus as part of initial maintenance regimen peaked in 2001; however it gradually declined to only 3% of kidney transplant recipients receiving it in 2009. In the same report at 1 year post transplantation, 6.5% of recipients were receiving sirolimus. The declining use of sirolimus can be attributed to the side effects

**6.12. Mechanism of action, metabolism and major drug interactions**

cases of pancreatitis have been described with azathioprine use.

coated MPA. [34]

**6.11. Azathioprine**

Anemia and thrombocytopenia can occur as well.

216 Current Issues and Future Direction in Kidney Transplantation

when used in combination with allopurinol.

**6.13. Adverse drug reactions**

encountered with medication usage.

**6.14. Sirolimus**

Similar to CNIs sirolimus binds to cytoplasmic protein FKBP-12 to mediate its action. The sirolimus/FKBP-12 complex then inhibits mTOR (mammalian target of rapamune). This en‐ zyme is a kinase that plays a key role in cell cycle progression (G1-S transition). Blocking mTOR has a profound effect on inhibiting T-cell proliferation and expansion. mTOR is ex‐ pressed ubiquitously so the antiproliferative effects of sirolimus is not limited to lympho‐ cytes and attributes to several adverse effects of the drug which are detailed below.

The anti-tumor effect of sirolimus is mediated by inhibiting the PI3K-AKT pathway which plays a critical role in cell proliferation, survival, migration and angiogenesis. [36] In addi‐ tion it inhibits growth of endothelial cells and tumor angiogenesis by interfering with syn‐ thesis of vascular endothelial growth factor.

#### **6.16. Clinical use**

Sirolimus has a long half life of 60 to 70 hours so consideration is needed when initiating the drug or making dose adjustments. Usually patients receive a loading dose of 3-15mg fol‐ lowed by once daily dosing of 1-5mg per day. The loading and maintenance dose are gener‐ ally determined by patient weight and immunologic risk. The dose is then adjusted based on drug levels. Therapeutic drug monitoring is routinely used with sirolimus. It is recom‐ mended to check 24 hour trough levels several days after initiation or dosage adjustment of sirolimus since it takes longer to achieve a steady state.

The drug is available as oral tablet at 0.5mg, 1mg and 2mgs dose. In addition there is also liquid formulation with strength of 1mg/ml. It is metabolized by CYP3A and hence dose needs to be adjusted in liver disease, but not in renal impairment.
