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What is the MOA of Cyclosporine?
- Reversible inhibition of T helper cells activation and proliferation by inhibition of IL-2
- Minimal inhibition of B cells, No inhibition of macrophages and neutrophils
T cell inhibition by cyclosporine is dependent on what factors?
Time and Dose
What place in therapy is Cyclosporine used?
- Not used for acute rejection
- Maintenance therapy only
What are the pharmacokinetics of Sandimmune (cyclosporine) specifically?
- Lipophilic – oil in water
- Bile needed for absorption
- F is variable
- Food delays absorption
What are the pharmacokinetics of Neoral (cyclosporine) specifically?
- F = consistent
- Bile and food DO NOT effect absorption
- Cmax is higher and earlier than with Sandimmune
What are the pharmacokinetics of Cyclosporine (generally)?
- Highly lipid soluble = accumulates in skin, organs and fat
- Vd = 3-5L (large)
- Use IBW or AdjBW
- Highly protein bound
- Enterohepatic recycling
- Use whole blood assays to measure drug levels
- CYP3A4 & pgp metabolism (>30 metabolites)
- Age effects metabolism
What are the dosing/admin concerns for Cyclosporine?
- IV: 2-6 mg/kg QD over 2-6 hrs
- IV:PO = 1:3
- Use glass or non-PVC bag (to avoid carcinogenic thiolate esters)
- Use Nitroglycerin tubing to prevent binding
- Sandimmune = 5-15 mg/kg divided BID PO
- Neoral or Gengraf = 2-10mg/kg divided BID PO
How should you instruct a patient to use Cyclosporine Oral (Sandimmune or Neoral)?
- Mix in beverage of choice (bad taste)
- Use glass cup
- Opened bottle is good for 2 months
- Take same time each day
- Avoid exposure to hot or cold
- Refill 1 week before out
- Take an extra bottle when traveling
What monitoring should be performed for Cyclosporine?
- Trough = 100-400 ng/mL, higher at first, lower with time, goals vary by transplant type
- Daily levels right after first dose and while titrating
How does Tacrolimus (FK506) compare to Cyclosporine (CsA)?
- Similar immunosuppression
- Better studied in liver transplant
- 100 more potent than CsA (= lower dose)
What are the pharmacokinetics of Tacrolimus (FK506)?
- F = erratic
- NO bile required for absorption
- Highly lipophilic
- 99% protein bound
- CYP3A4 metabolism
What are the dosing/admin concerns for Tacrolimus (FK506)?
- IV = 0.03-0.1 mg/kg QD continuous
- Oral = 1-20 mg PO QD, start 0.1 mg/kg/D
- Mix in glass or non-PVC
- Use IBW or AdjBW for oral dosing
- 0.5, 1 and 5 mg capsules
- IV:PO = 1:3
- Prograf = BID
- Astragraf XL = QD
What should you monitor for Tacrolimus (FK506)?
- 5-20 ng/mL
- Higher conc at first then lower
- Draw QD or 3x week during initiation and titration
What are the AE of Tacrolimus (FK506)?
- CNS: tremor, paresthesia, seizures, mental status changes
How does Tacrolimus AEs compare to Cyclosporine?
- Nephrotoxicity = similar
- Hepatotoxicity = Cholestasis similar to CsA
- CNS = higher incidence than CsA
What are the signs that nephrotoxicity is induced by a Calcineurin Inhibitor?
- > 6 weeks postop
- No fever
- Graft is non-tender
- Adequate urine output
- Gradual rise in SCr
What are the signs that Nephrotoxicity is due to an acute graft rejection?
- <4 weeks postop
- Graft tenderness
- Decreased urine output
- Rapid rise in SCr
How should HTN caused by a Calcineurin inhibitor be treated?
Is Tacrolimus (FK506) or Cyclosporine (CsA) more likely to cause HTN?
Is Tacrolimus (FK506) or Cyclosporine (CsA) more likely to cause HYPERglycemia?
- May require insulin thereafter