Immunosupressive uses
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Delicate balance
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Under immunosuppression risks
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Over immunosuppression risks
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Adult kidney transplantation
- 100,000 people on waiting list for kidney txp
- source of organ dictates how long kidney will survive
- 25,000 txp/year (most are deceased donors)
Maintenance therapy (start on day 1)
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Maintenance therapy goals
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T-cell activation process
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Calcineurin inhibitors (CNIs)
- binds to proteins cyclophilin or FKBP to inhibit calcineurin phosphatase
- complex inhibits de-phosphorylation of NFAT
- inhibits IL-2 gene transcription that activate T cells
CNIs
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Cyclosporin formulations
- Sandimmune (erratic bioavailability, variable absorption, nonlinear dose/conc response
- Neoral (less variability in absorption, more predictable dose/conc response)
Tacrolimus extended release
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CNI absorption
- sig intestinal CYP3A4/5 metabolism/Pgp transport (only absorb 30%)
- lower F in AA, Hispanics, children, CF, early post-txp
CNI distribution
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CNI dosing clinical pearls - doses/conc depend on:
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CNI therapeutic drug monitoring
Narrow therapeutic index (NTI) drugs
- 12 hour troughs in morning prior to AM dose
CNI TDM goals
- CSA trough: 100-400 ng/mL
- TAC trough: 5-15 ng/mL
Antiproliferatives
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Mycophenolate MOA
MPA inhibits IMPDH, rate limiting enzyme in purine synthesis for lymphocytes > blocks purine synthesis > inhibits proliferation of lymphocytes (T and B cells)
Mycophenolic acid
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Antiproliferative AEs
N/V, bone marrow suppression, diarrhea (Cellcept > Myfortic), birth defects, spontaneous abortion
mTOR inhibitors
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mTOR inhibitor MOA
interfere with cell signaling for cell proliferation and cell cycle
mTOR inhibitor AEs
delayed wound healing, HLD/hypertriglyceridemia, bone marrow suppression, proteinuria/nephrotoxicity, mouth ulcers, acne, interstitial pneumonitis/BOOP, edema, HTN, delayed recover from ATN
mTOR target troughs
- sirolimus: 6-8 ng/mL (>12 months: 4-6 ng/mL)
- everolimus: 3-8 ng/mL