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.