PHRX 4041 Immuno - Drug Therapy in Transplantation

which 3 transplants can have a live donor?

- lungs

- liver

- kidney

what are the most common causes of kidney transplants?

- diabetes

- hypertension

what is the most common cause of liver transplants?

hepatitis C

what are the most common causes of heart transplants?

- end stage heart failure

- hereditary condiions

- previous infection causing cardiomyopathy

- drugs

what are the most common causes of lung transplants?

- cystic fibrosis

- COPD

- pulmonary fibrosis

- pulmonary hypertension

who decides how to allocate organs?

UNOS

describe living donor organ donations

can either be living related or living unrelated

describe deceased donor organ donations

- brain death

- cardiac death; but has inferior outcomes

what are 3 risk factors for transplant rejection?

- sensitization (previous transplant, pregnancy, blood transfusions)

- VAD

- African american

overall, describe signal 1 of T cell activation during a transplant rejection response

- antigen recognition

- activates calcenurin

- turn on NFAR

- Il-2 production

overall, describe signal 2 of T cell activation during a transplant rejection response

- costimulation between CD28 and CD80/86

- full activation of T cell

overall, describe signal 3 of T cell activation during a transplant rejection response

- IL-2 binding

- mTor activated

- T cell proliferation

what are 3 goals of induction therapy?

- reduce incidence of acute rejection in 1st year

- treat and prevent delayed graft function

- delay initiation of CNI

which induction therapies are considered polyclonal?

antithymocyte globulin

which induction therapies are considered monoclonal?

- basiliximab

- alemtuzumab

which induction therapies are considered T cell depleting?

- anti thymocyte globulin

- alemtuzumab

which induction therapies are considered T cell NON depleting?

basiliximab

basiliximab brand name?

Simulect

describe MOA of basiliximab

binds to alpha chain of IL-2 receptor complex CD25 and inhibits IL-2 binding

describe ADEs seen with basiliximab

relatively few side effects

what 2 formulations of anti-thymocyte globulin are available? what are the differences

- thymoglobulin = rabbit derived

- atgam = equine

describe MOA of anti-thymocyte globulin

T cell depletion via complement depend cell lysis

what ADEs are seen with anti-thymocyte globulin?

- cytokine release syndrome

- serum sickness

- leukopenia and thrombosis

does anti-thymocyte globulin require premedication?

yes, required 30 mins prior to infusion

- APAP

- diphenhydramine

- steroids

compare thymoglobulin and atgam

- thymoglobulin is better for pt and graft survival

- atgam rarely used for solid organ transplant, high rates of batch inconsistency

alemtuzumab brand name?

campath

describe the MOA of

alemtuzumab

binds to CD52 on the surface of B and T cells causing apoptosis

describe ADEs seen with alemtuzumab

- infusion related reactions, better tolerated with SC admin

- IV admin is associated with cytokine release syndrome

- leukopenia and thrombocytopenia

when choosing an induction agent, when would you want to chose a T cell non depleting agent? (basiliximab)

- low risk of rejection = living donor, older age

- HIV, HepC

- liver transplant

when choosing an induction agent, when would you want to chose a T cell depleting agent? (antithymocyte globulin, alemtuzumab)

high risk of rejection:

- deceased donor

- comorbidies

- African american

- previous transplant

- younger age

what are 6 goals of maintenance therapy?

- reduce incidence of acute rejection

- prolong graft survival

- balacne infection risk

- minimize side effects

- facilitate adherence

what 2 classes of meds are used as main maintenance immunosuppression meds?

- CNIs (backbone meds)

- co stimulatory blockers

what 2 meds are CNIs?

- cyclosporine

- tacrolimus

cyclosporine brand names?

modified = neoral and gengraf

non modified = sand immune

- they are NOT interchangeable

tacrolimus brand names? which formulation is preferred?

- prograf

- astragraf XL

- envarsus XR

want to use ER forms = less ADES

describe MOA of CNIs

- work on signal 1

- form a complex that binds with calcenurin preventing expression of T cell activators

what are CNIs substrates of?

CYP3A4 and p-gp

what 2 ADEs are seen specifically with tacrolimus?

- pancreatic islet toxicity (diabetes)

- alopecia

what 5 ADEs are seen with both CNIs (tacrolimus and cyclosporine)?

- nephrotoxicity

- neurotoxicity

- hypertension

- hyperkalemia

- hypomagnesemia

what 3 ADEs are seen specifically with cyclosporine?

- hirsutism (hair growth)

- gingival hyperplasia

- hyperlipidemia

describe therapeutic drug monitoring for CNIs

- monitoring based on trough levels

- should measure levels 30 mins prior to next dose

- do not take CNI prior to blood draw

what trough levels are seen with tacrolimus?

5-15 ng/ml

what trough levels are seen with cyclosporine?

50-300 ng/mL

what drug is a co-stimulatiory blocker?

belatacept, acts on signal 2

belatacept brand name?

nulojix

how does belatacept work?

- binds to surface receptors CD80 and CD86 (B7 and B7-2) on antigen presenting cells

- inhibits interaction between APCs and T cells needed for T cell activation.

what is belatacept approved for?

only approved for kidney transplants

what BBW is seen with belatacept? what does this mean?

- post transplant lyphoproliferative disorder

- can only be used in Epstein Barr virus positive pts

what ADEs are seen with belatacept?

considered minimal compared to others

- anemia

- headache

- nausea, vomiting and diarrhea

compare belatacept to CNIS in terms of kidney function

belatacept shows much better kidney function over time

what 3 drug classes are often used as add on agents for maintenance immunosuppression?

- antiproliferatuve

- mTORi

- corticosteroids

what 2 drugs are considered to be anti proliferative/antimetabolites

- myophenolate

- axathioprine

what 2 formulations of mycophenolate exist? brand names?

- mycophenolate mofetil = cellcept

- mycophenolate sodium = myfortic

describe the MOA of mycophenolate

inhibits IMPDH and prevents de novo protein synthesis in lymphocytes

describe dosing conversions between mycophenolate agents

- cellcept 1000 mg = myfortic 720 mg

- cellcept IV to PO = 1:1

what 3 ADEs are seen with mycophenolate agents?

- GI (most common)

- leukopenia, thrombocytopenia, enamia

- teratogenic (has REMs)

describe the REMS program seen with mycophenolate

- exists since mycophenolate is teratogenic

- evidence of 1st trimester pregnancy loss and congenital malformations

- must provide education and contraception counseling

how should pregnancy be planned when using mycophenolate?

- stop medication for 6 weeks

- switch to alt med

azathioprine brand names?

- imuran

- azasan

- AZA

describe MOA of azathioprine

- incorperates into cellular DNA interfering with RNA synthesis and metabolism

- inhibits gene replication

- inhibits proliferation of promyelocytes in marrow

what mammalian target of rapamycin (mTORi) drugs are used for maintenance therapy?

- sirolimus

- everolimus

sirolimus brand name?

rapamune

everolimus brand name?

Zortress

describe the MOA of mTORis

- binds to mTOR which results in cell cycle arrest at G1

- inhibits proliferation of many cell line

what monitoring is required with mTORis?

monitoring for dose/trough levels

what are mTORis substrates of?

CYP3A4

when are mTORis considered for maintenance therapy?

- history of cancer

- intolerance to CNIs

- history of viral infections; BK virus

what overall consideration is taken with ADEs of mTORis?

have ALOT of ADEs, hard to tolerate

what corticosteroids are used as add on maintenance therapy?

- prednisone

- prednisolone

- methylprednisone

describe MOA of glucocorticoids

acute effects:

- decreased vasodilation and capillary permeability

- decreased leukocyte migration

upon binding to GRs:

= inhibit NFKB

- decrease pro inflammatory cytokines

- reduced B and T cells

- reduced APCs

what OTC meds should especially be avoided after transplant?

NSAIDS

what are 5 OTC meds that are safe after transplant?

- APAP

- diphenhydramine

- guafenisen

- colace

- Senna