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THERAPEUTIC DRUG MONITORING - SIROLIMUS
Presented by :B .Shiva Ranjini 11PD024
Sirolimus - a lipophilic macrolide immunosuppresant, which was isolated from a strain of fungus called Streptomyces hygroscopicus in 1972 September.
The compound was originally named rapamycin - an antifungal agent .
It was approved by the US Food and Drug Administration as an immunosuppresant in September 1999 and is marketed under the trade name Rapamune by Pfizer
Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.
Available dosage forms : tablet (0.5mg,1mg,2 mg,5mg) and solution(1mg/ml).
Available brands : Rapamune (US) ,rapacan (biocon, India) , sirova (intas)
Indication : Prophylaxis Of Organ Rejection In Renal Transplantation .
Contra indicated : Liver transplant, Lung transplant , High cholesterol patient , Hypersensitivity to sirolimus .
Pregnancy category : C
Pharmacokinetics : Cmax- 15 ng/ml Tmax- 1-3hrs (oral solution) and 1-6 hr (tablet) Cmin -7ng/ml Vd – 12 L/kg Bioavailability – 14 % (oral solution) ;41%
(tablet) Plasma protein bound – 92%
Metabolism -extensively in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen.
Elimination half life – 62 hours. Major excretion – feces 91 % Therapeutic range – 4-20 ng/mL . When given with
cyclosporine or tacrolimus the therapeutic range for sirolimus is generally
between 4 ng/dL to 12 ng/dL.
Mechanism of action – Sirolimus :
Antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation
sirolimus inhibits this process by binding to immunophilin , FKBP 12 to form an immunosuppresive complex
T Lymphocyte activation
TDM
Is TDM of sirolimus necessary ?
Blood sirolimus trough levels should be monitored:
In patients receiving concentration-controlled Rapamune (sirolimus).
In pediatric patients . In patients with hepatic impairment. During concurrent administration of inhibitors
and inducers of CYP3A4 and P-glycoprotein. If the cyclosporine dose is markedly reduced,
or if cyclosporine is discontinued.
What type of sample should be taken for assay ?
A whole blood trough sample should be used for the measurement of sirolimus concentrations – this should be collected as an EDTA anticoagulated sample .
How should sirolimus be monitored? High-performance liquid chromatography
(HPLC) and Immunoassay . Time of collection – trough concentration
<4h predose. Minimum collection volume – 3ml blood Storage – for 1 week at 4˚C - for >1 week at -20˚C
How often should sirolimus be monitored?
After a simple dose change, sirolimus measurements made before one week will be of little value. Once a steady state concentration has been reached trough concentrations can be monitored infrequently.