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.

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.