TRANSPLANT INTRO

maintenance therapy

• minimize/prevent acute and chronic rejection

• minimize immunosuppressant-assoc toxicities

• combinatorial therapy required in transplantation (multiple targets)

  • antimetabolites: azathioprine or MPA - reduces purine synthesis and decreases T-cell proliferation

  • calcineurin inhibitors: cyclosporine or tacrolimus - reduces IL-2 production and decreases T-cell proliferation

  • corticosteroids: prednisone vs steroid free - multiple mechanisms

  • mammalian target rapamycin (mTOR) receptor inhibitors: sirolimus reduces IL-2 production (not routinely used)

MPA

• indication:

  • solid organ transplantation

  • replaced AZA as “anchor” antimetabolite due to improved efficacy, increased pt/graft survival

• mechanism:

  • non-competitive binding to inosine monophosphate dehydrogenase

  • blocks guanosine nucleotide synthesis, reduces DNA polymerase activities

  • reduces T and B cell prolif

• fixed dosing (not does by BSA)

• mofetil and sodium NOT INTERCHANGEABLE

  • sodium made for pts who can’t tolerate mofetil

• AEs:

  • GI upset

    • switch MMF to EC-MPS to minimize stomach upset

    • split dose into QID dosing w/ food and snack

  • infections

  • hematological (-penias)

MPA PK

• absorption

  • diff behaviors b/w MMF and enteric-coated sodium (not interchangeable)

  • food decreases Cmax of both formulations; does NOT change AUC - consistency w/ food is key**

• distribution

  • drug monitoring in plasma

  • extensively bound to albumin

  • teratoenic** - use AZA in these pts

• metabolism and excretion

  • MMF is a prodrug → bioactivation → MPA

  • undergoes extensive intestinal and hepatic metabolism (conjugation) by UDP-glucuronosyltransferase 1A9 to form MPAG (inactive)

    • excreted into bile by multidrug resistant protein 2 (MRP2)

    • gets deconjugated in intestines by bacteria and gets recycled back into systemic circulation (entero-hepatic recirculation) → potential for DDIs

    • excreted into urine by OAT3 and MRP2 → potential for DDIs

    • when adjusting dose, wait 4 days then measure level

MPA DDIs

• antacids decrease absorption (AUC)

• cholestyramine decreases absorption (AUC)

• PPIs: same as above

• cyclosporine: decreases AUC (entero-hepatic recirculation) - need to increase dose of MPA if co-admin w/ cyclo (blocks recirculation of MPA = decreased MPA levels)

• abx: same as above - meropenem significant**** - reduces MPA exposure by several fold

• acyclovir: increases AUC (renal excretion)

MPA TDM

• not consistently practices, except for

  • active rejection

  • evidence of SEs

  • abnormal kinetics

• can draw 3 blood samples and use regression eq’n to estimate AUC in pt (limited sampling strategy)

• therapeutic range 30-60

• assume proportional dose response (double dose = double AUC)

• desired dose = (desired exposure/current exposure) x current dose

  • draw a level 4-5d later to make sure in therapeutic range

AZA (2nd line)

• indication: kidney transplant and RA; considered in severe MPA allergy/tox, pregnancy (absolute CI to MPA)

• MOA:

  • prodrug: AZA →6-mercaptopurine→ 6-thioguanine-nucleotide (halts lymphcyte DNA replication)

  • deactivationby xanthine oxidase (gout pts: allopurinol will raise AZA levels - MUST AVOID, colchicine probs only options), thiopurine S-methyltransferase (TPMT), and nudix hydrolase (NUDT15)

  • drug/gene interaction implications

• AEs

  • GI tox (food may help)

  • hematological tox

    • manage w/ dose reduction

    • dose-dependent liver tox

    • alopecia, pancreatitis (rare)

AZA PK

• absorption

  • consistency w/ food is key

• distribution

  • not extensively protein bound

  • distribute into placenta, but considered “acceptable” for use in kidney transplant pts planning pregnancy

• metabolism and excretion

  • hepatic glutathione S-transferase converts azathioprine to 6-mercaptopurine

  • hypoxanthine guanine phosphoribosyltransferase: converts 6-mercaptopurine → 6-thioguanine-nucleotide (TGN, ACTIVE, multi-step process)

  • deactivation of 6-mercaptopurine by xanthine oxidase and TPMT

    • allopurinol and febuxostate increase plasma [ ]’s

  • deactivation of TGN by NUDT15

  • urinary excretion of formed metabolites

AZA DDIs

• DDIs

  • xanthine oxidase inh; shunts metabolism to increase production of TGN → bone marrow suppression

• drug-gene interaxns (PGx)

  • TPMT

  • NUDT15

  • intermediate genes: dose reduce; if poor gene - need to avoid and find an alternative

• TDM not commonly done; monitor for clinical s/s, blood biochemistry