Sirolimus is an immunosuppressant that inhibits T-cell activation and proliferation, preventing rejection of transplanted organs. It is used to prevent renal transplant rejection when taken with cyclosporine and corticosteroids, targeting a blood concentration of 16-24 ng/mL for the first year and 12-20 ng/mL thereafter. Sirolimus has low oral bioavailability and a long half-life of 2.5 days, is highly protein bound, metabolized by CYP3A4 and primarily eliminated in the feces. Monitoring of liver enzymes, cholesterol, triglycerides and other parameters is required during treatment. Side effects include edema, hyperlipidemia, constipation and joint pain.

1. SIROLIMUS
Class: IMMUNOSUPPRESSANT
Mechanism of Action:
Inhibits T-cell activation and proliferation and
inhibits antibody production that occurs in
response to antigenic and cytokine
stimulation; inhibits T- cell proliferation by
inhibiting progression from the G1 to the S
phase of the cell cycle.
DOSE AND DOSAGE FORM
Prophylaxis of Renal Transplant
Rejection:Initiate with concomitant
cyclosporine and corticosteroids.Oral solution
and tablets interchangeable on a mg per mg
basis.Target whole blood trough
concentrations: 16-24 ng/mL for the first year
following transplantation; thereafter, 12-20
mg/Ml .
PHARMACOKINETICS
Absorption: Bioavailability: 14% (oral solution); 41% (tablet),Peak Plasma
Time: 1-3 hr (oral solution); 1-6 hr (tablet)
Distribution: Protein Bound: 92%,Vd:12 L/kg
Metabolism: CYP3A4
Elimination: Half-Life: 2.5 days,Excretion: feces (91%)
MONITORING PARAMETERS
Monitor LFTs and CBC during treatment. Monitor
sirolimus levels in all patients (especially in pediatric
patients, patients ≥13 years of age weighing <40 kg,
patients with hepatic impairment, and when
changing dosage forms of sirolimus. Also monitor
serum cholesteroland triglycerides, blood pressure,
serum creatinine, and urinary protein
INDICATIONS (FDA)
FDA approved use: prophylaxis of organ rejection in
patients receivingrenaltransplants.It can be used in
combination with other immunosuppressants
(cyclosporine, tacrolimus, glucocorticoids).Sirolimus
was one of two drugs used in first generation drug-
eluting intracoronary stents to inhibit neointimal
growth. Neointimal growth is caused by
inflammation, and is largely due to proliferation of
smooth muscle.
MAJOR SIDE EFFECTS
Peripheral edema, w/ corticosteroids (54-58%),Hypertriglyceridemia (45-57%; up to 90%
when used with or following cyclosporine),Hypercholesterolemia (43-46%; up to 90% when
used with or following cyclosporine),Constipation (36-38%),Arthralgia (25-
31%),Thrombocytopenia (14-30%).
MAJOR DRUG INTERACTIONS
Ketoconazole-Ketoconazoleincreases levels of
sirolimus by decreasing metabolism.
Mifepristone-Mifepristoneincreases levels of
sirolimus by affecting hepatic/intestinalenzyme
CYP3A4 metabolism. Contraindicatedwith CYP3A
substratesthat haveanarrowtherapeutic index.
CONTRAINDICATIONS
Sirolimus is contraindicated for use by patients
with a hypersensitivity to sirolimus.
Hypersensitivity reactions have been associated
with sirolimus administration.
-SPURTHIB.S