TRANSPLANT - CALCINEURIN INHIBITORS

tacrolimus (1st line)

• indication

  • solid organ transplant

• MOA:

  • binds to cytoplasmic immunophilins: FK-biding protein-12

  • tacro-immunophilin complex inhibits calcineurin

  • blocks acitivation/translocation of nuclear factor of activated T-cells (NFAT) → decrease transcription/translation/production of IL-2

  • decrease T-cell activation and T-cell proliferation

• dosed based on ABW

• AEs

  • [ ]-dependent

    • nephrotox

    • reversible, increase SCr, BUN, K+

      • delayed dosing; dose adjustment; avoidance of other nephrotoxic drugs (AGs, NSAIDs, vanco)

    • MOA: afferent arteriole renal vasocontriction → 30% decrease in eGFR

    • neurotox (HAND TREMORS, headache, peripheral neuropathy) - more likely than CSA**

    • alopecia (CSA causes hirsutism*)

    • diarrhea

    • post-transplant diabetes (more than CSA*)

    • hyperkalemia (monitor DDIs)

    • hypomagnesemia

  • non-[ ] dependent

    • anaphylaxis, allergic rxn to castor oil derivative in IV formulation

    • cardiac hypertrophy (rare)

tacro PK

• absorption

  • bioavail highly variable

  • affected by CYP3A4 and P-gp activity (lots of DDIs)

  • food decreases amount and rate of absorption (consistency is key*)

  • grapefruit juice decreases CYP3A4 and P-gp → increases bioavailability

  • diarrhea increases absorption → increases bioavail

    • pts are also on MMF which causes diarrhea (before adjusting dose manage diarrhea first)

• distribution

  • primarily in erythrocytes w/ typical blood:plasma ratio of ~35:1

  • use whole blood samples for TDM

  • protein bound to albumin and alpha 1-acid glycoprotein

• metabolism and excretion

  • extensively metabolized by CYP3A4/5 and transported by P-gp → drug/gene interactions

  • primarily fecal elimination

differential dx of acute rejection and cyclo/tacro nephrotoxicity

Acute rejection

• often <4wk post-op

• fever (sign of rejection***)

• HTN

• weight gain (kidney can’t get rid of fluids = fluid retention)

• graft swelling/tenderness

• decreased daily urine volume

• RAPID rise in SCr

• NORMAL CSA or TAC [ ]

• interstitial lymphocytic infiltrates

CSA or TAC Nephrotoxicity

• often >6wks post-op

• AFEBRILE

• HTN

• graft NONTENDER

• good urine output

• GRADUAL rise in SCr

• ELEVATED CSA ot TAC [ ]

• interstitial fibrosis, tubular atrophy, glomerular thrombosis, arterial inflamm

tacro DDIs (also applies to CSA*)

• increases TAC exposure (via CYP3A4 and Pgp inh):

  • azoles (voricon - much more potent inh**, fluc etc)

  • macrolides (erytho, clarithro) - azithro is the best of the worst

  • fluoroquinolones (floxacins)

  • non-DHP CCBs (verap, dilt)

  • ADs

• decrease exposure (via CYP3A4 and Pgp induction)":

  • abx (rifampin)

  • antiseizure meds

tacro TDM

• trough [ ] in whole blood; 2-3d until SS

• [ ]’s obtained from diff analytical assays are NOT interchangeable

• think about increasing the dose for pts w/ 1 or 2 copies of CYP3A5

cyclosporine

• indication

  • solid organ transplant (2nd line)

• MOa

  • binds to cytoplasmic immunophilins: cyclophins

  • cyclo-cyclophilin complex inhibits calcineurin

  • blocks activation/translocation of nuclear factor of activated T-cells (NFAT) → decreases transcription/translation/production of IL-2

  • decrease Tcell activation and proliferation

  • only diff from tacro is the binding protein**

• AEs

  • [ ]-dependent

    • nephrotox (no hand tremor like TAC)

    • neurotox (less than TAC)

    • HTN and hyperlipidemia (more than TAC)

    • hirsutism

    • gingival hyperplasia

    • hyperkalemia, hypomagnesemia

    • hepatotox (increase transaminases)

  • non [ ]-dependent

    • allergic rxns due to cremophor deriv in IV formulation

CSA PK

• absorption

  • bioavial highly variable

  • food decreases Cmax (consistency**)

  • metabolized by CYP3A4 and Pgp (grapefruit increases absorption**)

• distribution

  • distributes outside of vascular compartment

  • highly protein bound

  • cna distribute into placenta and breast milk

• metabolism and excretion

  • extensively metabolized by CYP3A4/5 and Pgp

  • primarily by biliary/fecal elimination

CSA DDIs

• same as TAC

• cyclo inhibits entero-hepatic recirculation of MPA and increases MPA clearance - need higher MPA dose***

• can inh CYP3A4, Pgp, organic transporter proteins → increase rhabdomyolysis (statins** pick rosuv)

CSA TDM

• trough [ ] in whole blood

• C2 level more accurate for estimating exposure

• target ranges tailored to each specific assay

which of following drugs can potentially decrease clearance of cyclosporine?

a) DHP CCBs

b) itraconazole

c) rifampin

d) marcolides

e) MPA