Tiêu đề 13. TDM OF DRUGS USED IN ORGAN TRANSPLANTATIONS.pdf ✅

PHARMD GURU Page 1 THERAPEUTIC DRUG MONITORING OF CYCLOSPORINE: GENERAL INTRODUCTION: Cyclosporine is a steroid-sparing immunosuppressant used in organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis, and atopic dermatitis. USES:  Cyclosporine is a calcineurin inhibitor and potent immunosuppressive agent.  It is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants.  It is also used for the treatment of patients with severe, active rheumatoid arthritis, with inadequate response to methotrexate and for the treatment of severe (i.e. extensive and/or disabling), recalcitrant, plaque psoriasis in adult, non-immuno-compromised patients who have failed to respond to at least one systemic therapy (e.g. PUVA, retinoids, or methotrexate) or for whom other systemic therapies are contraindicated or cannot be tolerated. MECHANISM OF ACTION: Cyclosporine acts mainly on the helper T-cells, which inhibits the activation of calcineurin and production of interleukin-2, thus reducing cell-mediated immune response. PHARMACOKINETIC PROFILE: ABSORPTION: The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects.  Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose.  The Cmax of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily. TDM OF DRUGS USED IN ORGAN TRANSPLANTATIONS
PHARMD GURU Page 2 DISTRIBUTION: The distribution of cyclosporine in the blood consists of 33% - 47% in plasma, 4% - 9% in the lymphocytes, 5% - 12% in the granulocytes, and 41% - 58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier. Protein binding: About 50% of the administered dose is taken up by erythrocytes while about 34% is bound to lipoproteins. METABOLISM: Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes. EXCRETION: After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6%of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, less than 1% of the dose is excreted as unchanged cyclosporine. HALF-LIFE (t1/2): The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours. ADR/TOXIC EFFECT:  Nervous system: Headache and paresthesia  Cardiovascular: Hypertension and edema  Dermatologic: Hypertrichosis  Endocrine and metabolic: Hirsutism, increased serum levels of triglycerides, and female genital tract disease
PHARMD GURU Page 3  Gastrointestinal: Nausea, diarrhea, gingival hyperplasia, abdominal distress, and dyspepsia  Genitourinary: Urinary tract infection  Infection: Increased susceptibility to infection and viral infection  Neuromuscular and skeletal: Tremor and leg cramps  Renal: Increased serum creatinine level and renal insufficiency  Respiratory: Upper respiratory tract infection. DRUG INTERACTIONS:  Cyclosporine level increases when used with diltiazem, doxycycline, erythromycin, ketoconazole, methylprednisolone (high doses), nicardipine, verapamil, or oral contraceptives; concomitant use should be avoided.  Cyclosporine level decreases when used with carbamazepine, isoniazid, phenobarbitone, phenytoin, or rifampicin; concomitant use should be avoided.  Risk of convulsion increases when Cyclosporine is used concurrently with high-dose methylprednisolone; concomitant use should be avoided.  Additive nephrotoxicity is observed when Cyclosporine is used with aminoglycosides, amphotericin B, ciprofloxacin, colchicine, melphalan, co- trimoxazole, or NSAIDs; concomitant use should be avoided. TOXIC RANGE: The oral LD50 in rats is 1480 mg/kg and the TDLO in humans is 12 mg/kg. CONTRAINDICATIONS: Contraindicated in • Hypersensitivity to Cyclosporine or any component of the formulation. • Hypersensitivity to polyoxyethylated castor oil. • Rheumatoid arthritis and psoriasis patients with abnormal renal function, uncontrolled hypertension, primary or secondary immunodeficiency other than that associated with autoimmune disease, uncontrolled infection, or malignancy (excluding non-melanoma skin cancer). • Concomitant administration with PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar, or radiation therapy in patients with psoriasis. • Concurrent use with bosentan.
PHARMD GURU Page 4 MONITORING PARAMETERS:  Monitor plasma concentrations of Cyclosporine.  Renal function tests (serum levels of creatinine and BUN).  BP (periodically and following the addition, modification, or deletion of other medications).  Monitor for hypersensitivity reactions (IV cyclosporine).  Signs and symptoms of hepatotoxicity, secondary malignancy, diabetes mellitus, and infection.  Monitor for progressive cognitive or motor deficits.  Magnetic resonance imaging may be required for the diagnosis of posterior reversible encephalopathy syndrome (PRES). TRANSPLANT PATIENTS:  Cyclosporine trough levels.  Serum electrolyte levels.  Renal and hepatic function tests.  BP.  Lipid profile.  Blood sugar level.  HbA1c. DOSAGE ADJUSTMENTS: HEPATIC IMPAIRMENT:  Mild-to-moderate impairment:  No dosage adjustments provided in the manufacturer's labeling; monitor blood concentrations.  Severe impairment:  No dosage adjustments provided in the manufacturer's labeling; however, metabolism is extensively hepatic (exposure is increased). Monitor blood concentrations; may require dose reduction. RENAL IMPAIRMENT:  Hemodialysis: Supplemental dose is not necessary. Dialysis does not significantly alter Cyclosporine clearance.  Peritoneal dialysis: Supplemental dose is not necessary.