Therapeutic drug monitoring of organ transplantation drugs
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1) The document discusses the therapeutic drug monitoring of cyclosporine, an immunosuppressant commonly used following organ transplantation. 2) Cyclosporine has variable absorption and significant inter-patient variability requiring therapeutic drug monitoring to maintain trough concentrations between 100-400 mcg/L. 3) Factors like CYP3A inhibitors/inducers and foods can impact cyclosporine levels, requiring dosage adjustments to be made based on concentration monitoring.
Therapeutic drug monitoring of organ transplantation drugs
- 1. TDM OF DRUGS USED IN ORGAN TRANSPLANTATION DR. RAMESH BHANDARI ASST. PROFESSOR DEPARTMENT OF PHARMACY PRACTICE KLE COLLEGE OF PHARMACY, BELAGAVI
- 2. Dr.RameshBhandari IMMUNOSUPRESSANTS Immunosuppressant are the drugs or class of drugs which reduce or suppress the body’s immune system. Also called as anti-rejection drugs. used in - Organ transplantation, - To treat auto-immune disease Psoriasis Rheumatoid Arthritis Crohn’s Disease
- 3. Dr.RameshBhandari CLASSIFICATION OF IMMUNOSUPRESSANTS Selective inhibitors of cytokine production and function Cyclosporine, Tacrolimus, Sirolimus Immunosuppressive antimetabolites Azathioprine Antibodies Daclizumab, Basiliximab, alemtuzumab Adrenocorticoids Prednisone, Prednisolone, methylprednisolone
- 4. Dr.RameshBhandari TDM OF CYCLOSPORINE Cyclosporine is a large lipophilic polypeptide that has been used for its immunosuppression acitvity. It inhibits T-lymphocytes and also inhibits production and release of lymphokines, including interleukin-2. Cyclosporine is indicated for the prevention of rejection in solid organ and marrow transplantation as well as for a variety of other disorders such as rheumatoid arthritis and Crohn disease. Cyclosporine can be administered intravenously or orally. The oral cyclosporine formulations has variable and incomplete gastrointestinal absorption and displays significant intra- and interpatient variability in bioavailability.
- 5. Dr.RameshBhandari DOSAGE FORM AVAILABILITY OF CYCLOSPORINE Dosage form Initial dose Maintenance dose IV 5-6 mg/kg single dose 5-6 mg/kg OD daily Oral 10-14 mg/kg single dose 5-10 mg/kg two divided dose
- 6. Dr.RameshBhandari GENERAL PHARMACOKINETIC PARAMETERS OF CYCLOSPORINE Absorption: oP-glycoprotein and cytochrome P4503A enzymes, respectively, affect the transport and metabolism of the antirejection agents cyclosporine, tacrolimus, and sirolimus. oIn addition to type of cyclosporine formulation, absorption may be impacted by first-pass metabolism, gastric motility, mode of administration, drug-drug, drug-herb, and drug–food interactions.
- 7. Dr.RameshBhandari GENERAL PHARMACOKINETIC PARAMETERS OF CYCLOSPORINE Distribution: Distributes widely into body fluids and tissues. In solid organ transplant recipients, the cyclosporine volume of distribution at steady state after IV dosing is 3–5 L/kg. Cyclosporine distributes in a concentration-dependent manner in blood: 41% to 58% in erythrocytes, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 33% to 47% in plasma. Cyclosporine crosses the placenta and is detected in breast milk. Cyclosporine is 90% bound to proteins (primarily lipoproteins), and approximately 50% of the drug in the blood is bound to erythrocyte.
- 8. Dr.RameshBhandari GENERAL PHARMACOKINETIC PARAMETERS OF CYCLOSPORINE Elimination: •Cyclosporine, tacrolimus, and sirolimus are extensively metabolized by the hepatic and gut cytochrome P-4503A enzyme systems (CYP3A) and counter-transported by P-glycoprotein. •Cyclosporine and its metabolites are eliminated principally through the bile, whereas 0.1% is excreted unchanged in the urine. •Patients receiving potent CYP3A and P-glycoprotein inhibitors may require a decreased dose or increased dosing interval. •Patients receiving potent CYP3A and P-glycoprotein inducers may require an increased dosage and a reduced dosing interval. •Dosing adjustments may be needed in hepatic failure for cyclosporine. Cyclosporine is highly metabolized by hepatic biotransformation into more than 25 metabolites.
- 9. Dr.RameshBhandari THERAPEUTIC RANGE Generally, the approximate desired values for cyclosporine trough concentrations on every 12-hour intervals is 100– 400 mcg/L. In solid organ transplantation, patients are maintained at the higher end of the therapeutic range initially, and then the desired concentration is often lowered over time to minimize nephrotoxicity and over-immunosuppression.
- 10. Dr.RameshBhandari APPROPRIATE SAMPLING TIME Cyclosporine blood concentrations should be assessed 3–5 days after initiation of therapy, a dosage adjustment, or initiation or discontinuation of known CYP3A inducers or inhibitors. Sampling times should be consistent and are usually obtained at 12 hour after a dose (trough). More frequent monitoring should be performed in patients who are hepatically impaired, children, or those with concomitant use of potent CYP3A inducers or inhibitors.
- 11. Dr.RameshBhandari PHARMACODYNAMIC MONITORING Concentration related toxicity: • Cyclosporine exhibits many concentration related toxicity which includes hypertension, nephrotoxicity and neurotoxicity, and these usually respond to dosage reduction. • Other toxicities include dermatologic, hepatic, gastrointestinal, and hematological effects. Non-Concentration related toxicity: • IV formulation is associated with sensitivity reactions due to the solubilizing agent Cremophor EL. Note: IV cyclosporine should be used only when oral therapy is not possible
- 12. Dr.RameshBhandari DRUG-DRUG INTERACTIONS In general, any co-administered immunosuppressant can potentiate the immunosuppression effects of other antirejection agents. Cyclosporine blood concentrations decrease when it is administered concomitantly with orlistat due to reduced absorption. Cyclosporine may decrease clearance of colchicine, digoxin, statins, and prednisolone resulting in toxicity of those drugs. Cyclosporine increases sirolimus blood concentrations; therefore, if used together, sirolimus should be administered 4 hr after cyclosporine.
- 13. Dr.RameshBhandari DOSE ADJUSTMENT Adjust the dose proportionately according to the desired serum concentration.