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Antiinfectives

General Rx

Renal Rx

Transplant Rx

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Educational

KidneyWorks

Clinical Tools

 

    Cyclosporine A (CSA)(Mol. wt = 1202.64) is an 11-amino acid cyclic peptide of fungal origin with strong immunosupressive actions. Its primary target appears to be the helper T lymphocytes, with little effect on other aspects of the immune response. However, because it acts early in the process of T cell activation, it has secondary effects on other cell types that are normally activated by factors produced by the T cells. See mechanism of action below

  Actions and Uses

Inhibits the production of interleukin IL-2 by helper T-cells thereby blocking T cell activation and proliferation (amplification of immune response). It is effective both in the prevention and in the treatment of ongoing acute rejection.
The current model for the mechanism of action of CSA (and tacrolimus) suggests that, in the T-cell cytoplasm, tacro binds to a specific binding protein called immunophilin which is actually a cis-trans isomerase. The CSA-immunophilin complex in turn binds to and blocks a phosphatase called calcineurin. The latter is required for the translocation of an activation factor (NF-ATc) from the cytosol to the nucleus, where it would normally bind to and activate enhancers/promotors of certain genes. In the presence of CSA (or tacrolimus), the cytosolic activation factor is unable to reach the nucleus, and the transcription of IL-2 (and other early activation factors) is strongly inhibited. As a result, T cells do not proliferate, secretion of gamma-interferon is inhibited, no MHC class II antigens are induced, and no further activation of the macrophages occurs.

  Available As

    IV: 50 mg / mL (5 mL)
    Oral :
    • Capsules For Microemulsion (Neoral): 25-mg or 100-mg
    • Capsules For Emulsion (Sandimmune): 25-mg, 50-mg, 100-mg
    • Solution For Microemulsion (Neoral): 100 mg/mL (50 mL)
    • Solution For Microemulsion (SangCya): 100 mg/mL (50 mL)
    • Solution for Emulsion (Sandimmune): 100 mg/mL (50 mL)
    According to the literature published by the manufacturer (Sandoz / Novartis), Neoral is a "microemulsion pre-concentrate" complete with a surfactant. The surfactant is included to reduce the variability of CSA absorption resulting from changes in bile flow. When placed in water, Neoral forms a homogeneous (optically clear) monophasic solution in which the droplet size remains less than 100 nm. This enhances CSA absorption significantly. Another product with virtually the same bioavailability as Neoral is SangCya.

  Dosage & Administration

Beginning several hours before TPX and during the first 1-3 days after TPX, cyclosporine (CSA) is usually administered by intermittent or continuous IV infusion (5 mg/kg/day). At SMH, the total dose is divided q 12 hrs and diluted in 250 mL D5W in a glass infusion bottle (maximum concentration 2.5 mg/mL). Each dose is infused over 2 - 4 hrs via non-PVC tubing, . When the pt is able to take oral medications, the infusion is stopped and oral CSA is started.

Oral dose @ 3 x IV dose

The oral dose also is divided q 12 hrs (usually at 8 AM and 8 PM); blood samples for plasma CSA level are normally drawn at about 6 AM.
Whether given orally or IV, the maintenance dose has to be adjusted to achieve the desired level of immunosupprssion which can vary depending on multiple factors including time after transplant, presence of infection, risk of rejection, etc. Target level = 100 - 350 mg/L.

  Kinetics

    Protein binding = 90 %. CSA is not dialyzable
    Vd = 4 - 6 L/kg; CSA crosses placenta and gets into mother's milk
    Absorption of oral CSA is incomplete, irratic, and depnedent on food and bile, but less so with the microemulsion (Neoral) whose absorption may be 20 - 50% higher than the regular emulsion preparation (Sandimmune). Neoral is not affected as much as Sandimmune by food or by clamping the T-tube.
    Oral bioavailability is highly variable (~25%). Time to Cmax= 1.6 - 6 hrs
    Metabolized extensively by liver (P450-IIIA4 ) and eliminated mainly in bile.
    t½ @ 12 hrs (range 6 - 24)

  Precautions

  • Increased susceptibility to bacterial, viral (e.g., CMV), and fungal infections.
  • Increased possibility of development of lymphoma
  • Do not administer concurrently with tacrolimus, OKT3, or ATGAM.
  • Increased risk of nephrotoxicity (avoid co-administration of other potentially nephrotoxic drugs).

  Pregnancy Risk Factor

    C.   This drug should be used only if the potential benefits justify potential risk to the fetus.

  Main side Effects

  • Nephrotoxicity; hypertension; hyperkalemia; hypomagnesemia; hyperuricemia
  • Headache, tremors, leg cramps, and convulsions.
  • Hirsutism, and acne.
  • Nausea/vomiting, abdominal pain, diarrhea, gingival hyperplasia

  Drug Interactions

  • Inhibitors and inducers of P450-IIIA4 (see table below) may alter rate of CSA metabolism and consequently its level. Dose adjustment should be guided by measured level.
  • Co-administration with amphotericin, aminoglycosides, or ganciclovir may enhance nephrotoxicity.
  • Grapefruit juice markedly enhances CSA bioavailability
  • Tropical fruits may inactivate CSA in the GI tract (see table below).

DrugsMechanism & Effect
Phenobarbital
Phenytoin
Rifampin and Rifabutin
Carbamazepine		 Þ P450 induction Þ ñ CSA metabolism;
Þ ò CSA level and òt½
Diltiazem and other CCBs
Erythromycin and Clarithromycin
Cimetidine and Metoclopramide
Danazol, Bromocriptine
Fluconazole and similar antifungals (K>I>M>F).
 Þ òCSA metabolism; ñt½
Þ ñ CSA level
Þ ñ immunosuppression & nephrotoxic effects
Grapefruit juice Inhibits CSA's metabolism in intestinal cells increasing its bioavailability and blood level.
Fresh Pineapple and Papaya Juices Contain enzymes (ananase and papain) that may inactivate ingested CSA in the GI tract.

 

  References

  1. Neoral Package Insert
  2. Gengraf
  3. Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001;38(6 Suppl 6):S25-35.
  4. Koomans HA, Ligtenberg G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation. 2001; 72(6 Suppl):S9-12.
  5. Campistol JM, Grinyo JM. Exploring treatment options in renal transplantation: the problems of chronic allograft dysfunction and drug-related nephrotoxicity. Transplantation. 2001;71(11 Suppl):SS42-51.

 

 
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