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PHRM 865 > Solid Organ Transplant - Maintenance Immunosuppression > Flashcards

Solid Organ Transplant - Maintenance Immunosuppression Flashcards

(52 cards)

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1
Q

What are the classes of maintenance agents?

A

calcineurin inhibitors
antimetabolites
mTOR inhibitors
corticosteroids
T-cell co-stimulation blocker

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2
Q

What are the calcineurin inhibitors?

A

cyclosporine
tacrolimus

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3
Q

What are the antimetabolites?

A

azathioprine
mycophenolate mofetil
mycophenolate sodium

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4
Q

What are the mTOR inhibitors?

A

sirolimus
everolimus

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5
Q

What are the corticosteroids?

A

methylprednisolone
prednisone
dexamethasone

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6
Q

What are the T-cell co-stimulation blockers?

A

belatacept

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7
Q

What is the MOA of calcinuerin inhibitors?

A
  • Induces immunosuppression by inhibiting signal-1of T-cell activation
  • Inhibition of calcineurin phosphatase enzyme within the T-cell –> prevents subsequent T-cell activation
  • inhibit calcineurin, thus preventing NFAT activation
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8
Q

What class is the cornerstone of immunosuppression?

A

calcineurin inhibitors
- Most commonly utilized immunosuppressants
- Improves survival, reduces hospitalization, reduces patient morbidity

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9
Q

What are the formulations of cyclosporine?

A

non-modified: sandimmune - poor and erratic bioavailability
modified microemulsion: neoral and gengraf - improved bioavailability = increased AUC
NON-modified and modified are NOT interchangeable

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10
Q

What is the therapeutic drug monitoring of cyclosporine?

A
  • Intersubject variability of CsA exposure (AUC) ranges 20-50%
  • Goal 12-hr trough ranges~100-400ng/mL
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11
Q

What are the formulations of tacrolimus?

A
  • Immediate-Release: Prograf
  • Extended-Release: Astagraf XL, Envarsus XR
  • Potential benefits to ER dosing: lower overall drug dose, improved adherence, less peak effects = reduced ADE, less swings/variability in trough concentrations
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12
Q

What is the therapeutic drug monitoring for tacrolimus?

A
  • 50x more potent than cyclosporine
  • Goal 12-hr trough ranges ~5-15ng/mL
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13
Q

Prograf

A

Immediate release caps or suspension
Given BID
Oral, sublingual, intravenous
* Not a 1:1 conversion!
* 2mg PO = 1mg SL = 0.33mg IV
* IV: continuous infusion

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14
Q

Astagraf

A

Extended release caps
Given DAILY
fallen out of favor due to PK profile

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15
Q

Envarsus

A

Extended release tabs
Given DAILY
Not a 1:1 conversion between formulations!
* 1mg total daily dose of Prograf = 0.8mg total daily dose of Envarsus

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16
Q

What is the metabolism of cyclosporine?

A

metabolism:
- Cytochrome P450 (CYP) 3A4
and P-glycoprotein
- CYP3A4 and P-glycoprotein inhibitors –> INCREASE CsA exposure
- Prone to multiple drug-drug interactions!

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17
Q

What is the elimination of cyclosporine?

A
  • T1/2 highly variable (10-40 hr)
  • Prolonged in hepatic disease or
    disorders of biliary excretion
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18
Q

What is the metabolism of tacrolimus?

A
  • Cytochrome P450 (CYP) 3A4
  • CYP3A4 inhibitors –> INCREASE
    FK exposure
  • Prone to multiple drug-drug
    interactions!
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19
Q

What is the elimination of tacrolimus?

A
  • T1/2 more consistent (12-18 hr)
  • Prolonged in hepatic disease or
    disorders of biliary excretion
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20
Q

What are the AEs of cyclosporine?

A

HTN, hypercholesterolemia, hypertriglyceridemia, gingival hyperplasia, hirsutism

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21
Q

What are the AEs of tacrolimus?

Study These Flashcards
A

neurotoxicity (HA, insomnia, tremor, dizziness); hyperglycemia, post-transplant diabetes mellitus; alopecia

22
Q

What are CYP450 enzyme inducers?

Study These Flashcards
A

results in decreased CSA/FK concentrations
* Phenytoin
* Carbamazepine
* Phenobarbital
* Rifampin

23
Q

What are CYP450 enzyme inhibitors?

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A

results in increased CSA/FK concentrations
* Erythromycin, clarithromycin
* Azole Antifungals
* Diltiazem, verapamil
* Ritonavir
* Grapefruit juice

24
Q

Liver dysfunction in CNIs lead to what?

Study These Flashcards
A

alterations in CNI PK
* Tacrolimus primarily eliminated by hepatic metabolism
* T 1⁄2 prolonged

25
Renal dysfunction in CNIs leads to what?
no change in CNI PK * Very minimal urinary excretion of drug * Dose adjustments not necessary for patients receiving forms of renal replacement (HD, PD, CRRT)
26
What is the MOA of azathioprine?
targets the cell cycle MOA: AZA converted to 6-MP in blood --> 6-MP incorporated into nucleic acids --> inhibition of RNA and DNA synthesis --> inhibition of immune cell proliferation
27
What is the therapeutic drug monitoring of azathioprine?
no routine TDM Ability to measure metabolite (6-thioguanine nucleotide) if needed
28
What are the AEs of azathioprine?
- GI: abdominal pain, N/V, diarrhea, dyspepsia - Bone marrow suppression: agranulocytosis, macrocyticanemia, leukopenia, neutropenia, thrombocytopenia
29
What are the drug interactions of azathioprine?
less common than CNIs allopurinol and febuxostat
30
What is the MOA of mycophenolic acid?
targets nucleotide synthesis most commonly used adjunct agent with CNIs Inhibits the de novo pathway of purine synthesis, (selective for lymphocytes) --> limits progression of activated T and B cells
31
What is the metabolism of mycophenolic acid?
- Immediately hydrolyzed to form free MPA, the active compound - Most of the free MPA is conjugated in the liver by glucuronyl transferase
32
What are the formulations of mycophenolic acid?
mycophenolate mofetil, MMF: produrg, immediate release (stomach) mycophenolate sodium, MPS: enteric coated, delayed release (small intestine) Therapeutically equivalent & interchangeable but dosing requires conversion MMF 250mg = MPS 180mg IV:PO = 1:1 TDM is controversial!
33
What are the AEs of mycophenolic acid?
- FDA pregnancy category D (teratogenic) * Formal consent required for women of childbearing potential (REMS program) * 2 forms of birth control required
34
What are the drug interactions of mycophenolic acid?
- Aluminum-/magnesium-containing antacids (decreases MPA AUC) - Cholestyramine (decreases MPA AUC) - Other myelosuppressive drugs such as valganciclovir, sirolimus (additive myelosuppression)!! - Cyclosporine
35
What are the structures of sirolimus and everolimus?
- Sirolimus = structural analog of tacrolimus - Everolimus = structural analog of sirolimus
36
What do the mTOR inhibitors act with?
* Acts synergistically with other immunosuppressants - Combination with CNI and/or corticosteroids - Minimal overlapping toxicity
37
What is the MOA of mTOR inhibitors?
Binds to FKBP12, which fuses with mTOR --> inhibits T-cell proliferation
38
What is the metabolism of mTOR inhibitors?
Metabolism: CYP 3A4 & P-glycoprotein - Same DDI as CNIs
39
What is sirolimus approved for?
kidney transplant rejection prophylaxis goal trough ~5-10 ng/mL
40
What is everolimus approved for?
kidney & liver transplant rejection prophylaxis goal trough ~3-8 ng/mL
41
What are the AEs of mTOR inhibitors?
edema, hyperlipidemia, hypertriglyceridemia, impaired wound healing, mouth ulcers, proteinuria
42
What are the limitations to mTOR inhibitors?
- Impaired wound healing --> unable to use immediately post-op - Sirolimus: increased risk of hepatic artery thrombosis post-op - Everolimus: increased risk of kidney arterial and venous thrombosis post-op
43
What are mTOR inhibitors used adjunctly with?
- Replace CNIs in patients with toxicity (nephrotoxicity) - In combination with CNIs to use lower levels of both drugs - Replace mycophenolate in patients with intolerable ADE - Steroid-free protocols
44
When will mTOR inhibitors NOT be used immediately?
Will NOT be used immediately post-transplant due to impaired wound healing
45
What was the original cornerstone of immunosuppression?
corticosteroids * Corticosteroid dosage is tapered to a low dose or completely off post- transplant * Some transplant centers utilize early steroid withdrawal or steroid-free regimens
46
What is the MOA of corticosteroids?
- Inhibits cytokine production by T cells and macrophages - Blocks transcription of cytokine genes including interleukins 1, 2, 3, 5, TNF-alpha, and interferon gamma - Interferes with cell migration, recognition, and cytotoxic effector mechanisms
47
What are the AEs of corticosteroids related to?
both average dose and cumulative duration of use
48
What is belatacept contraindicated in?
Relative contraindication for use in liver transplant --> increased graft loss and death
49
What is the MOA of belatacept?
- Blocks signal-2 of T-cell activation(“co-stimulation”) - Blocks the CD28 mediated co-stimulation of T-lymphocytes by binding to CD80 and CD86 on APCs - Inhibits T lymphocyte proliferation and cytokine production
50
What is unique about the administration of belatacept?
IV only Routinely Q4weeks at an infusion clinic = guaranteed adherence!
51
What is belatacept's place in therapy?
Replacement or adjunct to CNI
52
What are the AEs of belatacept?
- Post-transplant lymphoproliferative disorder (PTLD) * 9x-fold higher rate in those who were Epstein-Barr Virus (EBV) seronegative * Contraindicated in EBV seronegative patients!!

PHRM 865 (61 decks)

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