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PDAT4 > 22/23 - Transplant Therapeutics > Flashcards

22/23 - Transplant Therapeutics Flashcards

1
Q

3 Mechanisms for IMMUNOSUPPRESSION

A

IMS is achieved by:
DEPLETION of Lymphocytes

DIVERSION of lymphocyte Traffic

BLOCKING of lymphocyte proliferation & response

Combination works best:
typically 3 maintanence Drugs
or AB induction + 2 maintanence druge

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2
Q

Induction Overview
Strategy for ImmunoSuppression: INDUCTION

A

Acute & Potent IMS

Used in PERI-operative Period

Goals:
induce allograft acceptance by Supressing T-Cells
BRIDGE to Maintenance Agents

Agents:
Corticosteroids
Lymphocyte Depleting & Non-Depleting ANTIBODY AGENTS

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3
Q

Corticosteroids: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A

NON-Depleting Agent
universally used for ALL xplants @ time of engraftment

  • *Action on T-cells**
  • *inhibit the TRANSLOCATION of NFkB & AP-1** –> nucleus
  • INHIBITION of CYTOKINE GENE EXPRESSION*

Act on Other Leukocytes

Anti-inflammatory Effects

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4
Q

Corticosteroids: Dosing / Admin
Strategy for ImmunoSuppression: INDUCTION

A

HIGH DOSE METHYLPREDNISOLONE

250-100mg IVPB
or
Followed by IV MP or PO prednisone taper

Supresses lymphocyte production for 24 hours
allows for QD dosing

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5
Q

Corticosteroids: ADRs
Strategy for ImmunoSuppression: INDUCTION

A

SHORT TERM EFFECTS
most resolved after 1-2 days

  • impaired*
  • *Glucose Tolerance /** Wound Healing

INCREASED
Appetite / BP / Fluid Retention

Mood Disturbance

Leukocytosis

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6
Q

Depleting Agents: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A
  • *Polyclonal Antibodies**
  • *ThymoGlobulin // Atgam**

AB’s directed against T-Cell surface AG’s –> Binding
VVV
Opsonization & elimination
VVV
T-Cell Lysis + Cytokine Release
VV
T-CELL DEPLETION

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7
Q

Thymoglobulin & Atgam
Dose & Admin
Strategy for ImmunoSuppression: INDUCTION

A

DEPLETING AGENTS

Thymoglobulin
30 day half life // IV for 3-7 days // 1 IgG Subtype
Binds to lymphocytes with GREATER AFFINITY
–> Greater/longer T-cell Depletion

Atgam
Same, but with 2 subtypes
Different binding affinities

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8
Q

Polyclonal AB’s: ADR’s
Thymoglobulin / Atgam
Strategy for ImmunoSuppression: INDUCTION

A

Leukopenia / Thrombocytopenia / Anemia
Some AB’s recognize AG’s on NON-lymphoid Cells

MAY trigger T-cell Activation
foreign protein / pro-inflammatory cytokines / POLYclonal response

Cytokine Release Syndrome
first dose effect

Serum Sickness
type 3 hypersensitivity, 5-15 days after admin, may use coritocosteroids

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9
Q

Polyclonal AB’s - MONITORING
Thymoglobulin / Atgam
Strategy for ImmunoSuppression: INDUCTION

A

EFFICACY - GOALS
Absolute Lymphocyte Count (ALC) of < 200 cells/uL
(better surrogate marker vs CD3)
CD3 < 50 cells/uL

TOXICITY
WBC < 5k
Platelets <100k
due to nonspecificity of AB –> non-lymphoid cells

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10
Q

Alemtuzumab: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A

Monoclonal AB // DEPLETING AGENT

Humanized AB against CD52

CD52 found on nearly ALL T+B cells
+ most monocytes / macrophages / some granulocytes

AB-Dependent LYSIS after Cell surface binding

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11
Q

Basiliximab: Pharmacology
Strategy for ImmunoSuppression: INDUCTION

A

Monoclonal AB // NON-DEPLETING AGENT

Chimeric AB against CD25 // aka IL-2 Receptor Antagonist

CD25 = A-Chain on ACTIVATED T-cells only
VVV
blocks signal 3 & T-cell proliferation

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12
Q

Alemtuzumab: Dose / ADRs
Strategy for ImmunoSuppression: INDUCTION

A

single 30mg Dose on day 0
12 day half life
prolonged lymphopenia

Infusion Reactions
fevers / chills / HypoTension / Rash / NVD
use APAP / DPH / MP to limit ADR

Hematologic
Due to targetting OTHER cell lines
anemia / neutropenia / thrombocytopenia
Use: Erythropoetin / filgrastim / transfusion

Infections
opportunistic // sepsis

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13
Q

Basiliximab: Dose / ADRs
Strategy for ImmunoSuppression: INDUCTION

A

20mg IVPB on Day 0 + 4
7 day half life

IL-2 Receptor saturation for 30-45 days

  • *EXTREMELY WELL TOLERATED**
  • no Cytokine release syndrome or first dose reaction*

RARE Hypersensitivity Reactions

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14
Q

Calcineurin Inhibitors (CNIs): Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

A

FORMULATIONS are NOT INTERCHANGABLE
medication errors result in serious ADRS –> graft rejection

Tacrolimus = TAC or FK506
Binds FKB-12 –> complex

Cyclosprine = CSA
Binds -> Cyclophilin

INHIBIT CALCINEURIN –> prevent NFAT from entering nucleus
VV
Inhibition of IL-2 synthesis –> Prevention of T-cell Proliferation

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15
Q

Tacrolimus Dosing
Strategy for ImmunoSuppression: MAINTENANCE

A

Dose adjustments are based on TROUGH LEVELS (C0)

  • *Prograf**
  • *IR** 0.05-0.1 mg/kg/dose PO q12 hr
  • *Astagraf-XL**
  • *ER** 0.1-0.2 mg/kg/dose –> 1:1 conversion
  • *Envarsus-XR**
  • *ER, but with better absorption (throughout GI tract**)
  • *1:0.8 conversion**
  • reduced daily IR dose by 20%*
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16
Q

Cyclosporine: Dose
Strategy for ImmunoSuppression: MAINTENANCE

A

Cyclosporine dose adj based on
TROUGH (C0) or 2-hr PEAK level (C2)

Cyclosporine -> Cyclophilin

3-5 mg/kg/dose PO q12h

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17
Q

CNIs: Routes of Administration
Strategy for ImmunoSuppression: MAINTENANCE

A

IV Formulation
↑Risk for NEPHROtoxicity, avoid formulation
used for bone marrow xplant w/ severe Mucositis

Suspension
given via NG tube

Sublingual
admin of IR TAC only –> decrease dose by 50%

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18
Q

CNI: Drug Interactions
Strategy for ImmunoSuppression: MAINTENANCE

A
  • *CYP3A4 inducers** reduce levels of CNI
  • phenytoin / carbamazepine / rifampin*
  • *CYP3A4 inhibitors** INCREASE levels of CNIs
  • *Azole antifungals / -mycins** / diltiazem / verapamil / ritonavir

p-GP substrate

NSAIDS –> added nephrotoxicity

ACE-I / ARB –> renal sparing / nephroprotective effects

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19
Q

TAC vs CSA
in ADRs

A

Both still have 5-yr risk of CHRONIC RENAL FAILURE = 7-21%

TAC is WORSE at almost ALL, except HTN

Acute Nephrotoxicity
generally similar in ACUTE setting
vasospasms of glomerular arteriole –> reduction in GFR
reversible

Chronic Nephrotoxicity
IRREVERSIBLE
ischemia due to hemodynamic changes -> scaring/fibrosis

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20
Q

When to choose or switch
CSA > TAC ?

Every time you switch IMS agents you increase risk of rejection
Check levels 7 days after change and then monthly!

A

RISK FOR DM
Post Transplant DM (PTDM) / New Onset Diabetes after transplant (NODAT)
TAC has dose dependent REDUCTION in INSULIN secretion

PEDS < 5 YEARS
use CSA, not TAC

Hair Loss

Tremors or Falls

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21
Q

When to choose or switch
TAC > CSA?

Every time you switch IMS agents you increase risk of rejection
Check levels 7 days after change and then monthly!

A

GREATER POTENCY
​REJECTION

  • *Hair Growth (hirutism**)
  • caused by CSA*

Gingival HyperPlasia

22
Q

AntiMetabolites: Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

A

Stop the CELL-CYCLE for T-cell Proliferation

Mycophenolic Acid = MPA
INHIBITS IMPDH –> inhibits DE-NOVO synthesis of Guanosine
MORE SPECIFIC, only blocks the DE-NOVO pathway
higher affinity to IMPDH of ACTIVE T-cells

Azathioprine = AZA
prodrug, same de-novo inhibition but for BOTHadenine + guanine
TPMT + Xanthine Oxidase for inactivation

23
Q

AZA: Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

A

AntiMetabolite Maintenance Agent // PRODRUG

INHIBITION of DE-NOVO Purine Synthesis
(both ADENINE + GUANINE)

Need for TPMT SCREEN (genotyping / enzyme activity test)
since this is responsible for activation & deactivation of 6MP

  • *TPMT genetic Polymorphisms**
  • SLOWS inactivation of 6MP* –> accumulation of myelosuppressive metabolites –> death!
24
Q

Mycophenolate: Dose / Admin / ADR
Strategy for ImmunoSuppression: MAINTENANCE

A
  • *PO: 1000-1500mg BID**
  • 720mg EC-MPS = 1000mg MMF (**dose conversion)*

IV: 1000mg BID over 2 hours

  • *MPA has SECOND PEAK** due to ENTEROHEPATIC RECIRCULATION
  • BUT –>* CSA INHIBITS that –>
  • decreased AUC of MPA when taken with CSA*

ADR:
GI Upset // Hematologic

25
Q

Azathioprine: Dose / Admin / ADR
Strategy for ImmunoSuppression: MAINTENANCE

A

PO: 1-3 mg/kg/day

IV: EQ to oral dose, but lower end

  • *AVOID WITH XANTHINE OXIDASE INHIBITORS**
  • Uloric / Allopurinol*
  • NOT as potent as MPA*
  • *HEMATOLOGIC EFFECTS** (not as specific)

Pancreatitis / Hepatoxicity / Squamous Cell Cancer

26
Q

MPA: GI ADR Amelioration

A

MPA = GI ADR’s

Take W/ FOOD // use Anti-motility agents or Anti-emetics

Change to EC formulation (for upper GI ADR)

SWITCH TO AZA? (rejection risk, not as potent)

TID-QID Dosing Intervals

  • reduce MPA dose*
  • but increased incidence of rejection*
27
Q

CorticoSteroids for Maintanence
Strategy for ImmunoSuppression: MAINTENANCE

A

Prednisone: 5-15mg/day (low dose)

Reserved for:

  • *Pts w/ multiple rej** on steroid-free regimin
  • *High-Risk xplant Patients (sensitized**) or +xmatch
  • *No-Induction - 3 drug regimen**

ADR’s Associated w/ CHRONIC USE
Diabetes / Osteoporosis / HYPERLipidemia / Cateracts
Acne / Infection / Weight Gain

28
Q

Risks & Benefits of
Steroid Minimization / Avoidance
Strategy for ImmunoSuppression: MAINTENANCE

A

BENEFITS
Reduction of PTDM/NODAT (Diabetes from Steroids / CNIs)
less weight gain, no diff in infxn rates

RISKS
Need for higher doses of other immunospression (^TAC/CSA)
More Potent Induction

29
Q

mTOR inhibitors: Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

A

Sirolimus** // **Everolimus

  • unlike CNI’s who block IL-2 Production*
  • *mTORi block IL-2 Signal Transduction**

mTOR inhibits binds to FKBP-12
the complex inhibits phosphorylation of proteins

Inhibits smooth muscle proliferation

inhibits VEGF activity
possible benefit in reducing malignancies

30
Q

Sirolimus / Everolimus
Dose & Admin
Strategy for ImmunoSuppression: MAINTENANCE

A

both mTORi’s have NO IV formulation

Sirolimus
QD, LD of 6mg or 0.2mg/kg
MD of 2mg or 0.1mg/kg
62 hour Half Life

Everolimus
BID Dosing , NO loading dose
MD of 0.75mg q12 hr
Half life of 30 hours

31
Q

mTORinhibitors: ADR’s
Sirolimus / Everolimus
Strategy for ImmunoSuppression: MAINTENANCE

A

Hematologic
Thrombo / Anemia

Mouth Ulcers / Decreased Wound Healing
Since inhibition of VEGF healing
–> delay initiation / if recurrent DC

Proteinuria / Nephrotoxicity
GFR decreased by 15% in setting of Full dose CNI (CSA>>FK506)
Lower CNI through,conversion of CNI -> Sirolimus not recommended

HYPERTg’s // Interstitial Pneumonitis

32
Q

mTORinhibitors: Drug Interactions
Sirolimus / Everolimus
Strategy for ImmunoSuppression: MAINTENANCE

A

P-Glycoprotein Competition
CYCLOSPORINE –> resulting in INCREASED BV/Levels
admin 4 hours after CSA

CYP3A4 Inducers –> decrease mTORi levels
Phenytoin / carbamazepine / rifampin / nafcillin

CYP3A4 inhibitors –> INCREASE levels
Azole antifungals / -mycins / diltiazem / ritonavir

33
Q

Belatacept: Pharmacology
Strategy for ImmunoSuppression: MAINTENANCE

A

Selective Costimulation Blocker
Signal 2 Blocker

Fusion Protein –> B7 on APCs
promotes T-cell anergy & apoptosis

Benefit:
Preserve RENAL FUNCTION (CNI avoidance)

34
Q

Belatacept: Dose & Admin
Strategy for ImmunoSuppression: MAINTENANCE

A

IV Dosing over 30 minutes
Month 0-1: 10mg/kg –> Month 2-3: 10mg/kg –> Month 4-12: 5mg/kg

EBV Seropositive Virus Patients ONLY
Epstein-Barr Virus

DO NOT USE in LIVER XPLANT patients
due to an INCREASED risk of graft loss & death

35
Q

Belatacept: ADRs

A

PTLD
only used in EBV Positive because of this
B-cell proliferation due to induced immunosupression

Myelosuppression

GI Upset

Neuropathy

Acute Infusion Related ADR’s

36
Q

Triple Regimen
Immunusppressive Therapy

A

If deviating from golden Triad
MUST compensate for increased REJ RISK
VVV
3 Maintenance Drugs
AB Induction + 2 Maintanence Drugs

37
Q

Patient Factors in OPTOMIZING IMS

A

Perceived Immunologic risk for rejection

Expected/existing drug toxicities

Infectious Risk

Co-morbidities

H/O of non-adherence

38
Q

Antibody Induction Choice

HIGH RISK

A

High Risk:
African / Re-Transplant / High PRA
ABOi / Positive XM

use:
LYMPHOCYTE DEPLETING AGENTS

Thymoglobulin / Atgam / Alemtuzumad

39
Q

Antibody Induction Choice

LOW RISK

A

No Antibody
need to stay on the 3 drug regimen

Basiliximab
can be 2 drug Therapy

High Risk for ATN/DGF
upgraded to depleting agents

40
Q

Acute Tubular Necrosis = ATN

Who is at risk?

A

ATN –> damage to kidney tubules
caused by a lack of oxygen to kidney tissue = ischemia

Risk Factors:

  • *Donor Age >50 or <12** yo
  • *Recipient >55**
  • *Cold Ischemic time > 24 hours**
  • *Donor SrCr > 1.8mg/dL** prior to procurement
  • *DCD** (donation after cardiac death)

IF AT RISK for TBN:
Use depleting agent –> result in decreased inflammatory response & improved outcomes

41
Q

Thymoglobulin vs Atgam
For AB Induction in KIDNEY

A
  • *THYMOGLUBULIN** > Atgam
  • less rejection* & improved graft survival
42
Q

Thymoglobulin vs Alemtuzumab
for AB induction for KIDNEY

A

HIGH RISK = similar

  • *Alemtuzumab
  • LESS rejection* in EARLY rejection**
  • BUT*
  • *MORE LATE-acute rejections**
  • *“Alem is MORE late”**

both beneficial in ATN/DGF prevention following kidney transplant

43
Q
  • *Alemtuzumab vs Basiliximab**
  • *AB Induction for KIDNEY**
A
  • low risk:*
  • *ALEMTUZUMAB**
  • LESS rejection*

but more LATE-acute rejections w/ alemtuzumab

“Alem is MORE LATE”

44
Q
  • *Thymoglobulin vs Basiliximab**
  • *AB Induction for KIDNEY**
A

HIGH RISK:

  • *THYMOGLOBULIN**
  • LESS rejection*

more overall infections with thymoglobulin though

45
Q

CSA vs TAC
Maintenance Selection

A
  • *TAC is better for all organs**
  • but EQUAL for HEART*

Cyclosporine
higher LDL / hirsutism / gingival HYPERplasia / HT

Tacrolimus
higher incidence of NODAT, Alopecia, Neurotoxicity

no consistance differences in
mortality / infection / delayed graft fxn

46
Q
  • *Belatacept vs CNI**
  • *Maintenance Selection**
A

Bela allows for avoidance of CNI nephrotoxicity

  • *for Kidney:**
  • *Bela is EQUAL in survival of graft**

BELA > CNI
for LONG-TERM renal fxn (GFR)
but has increased risk of ACUTE rejection

47
Q

Steroid Minimization / Avoidance
What is the best ADJUNC agent combination?

A

Steroids
additional safety in case of nonadherence
allows for a SAFER dose de-escalation of CNI and MPA in case of ADRs

if STEROID-FREE
use AB-induction

  • if deviating from TAC/MPA combo*
  • *consider steroids**, esp for high-risk
48
Q

MMF (MPA prodrug) vs AZA
Maintenance Selection

A

NO difference in patient survival or graft function

MMF (MPA prodrug) is….
less ACUTE rejection
improved GRAFT survival
more diarrhea / similar other side effects

49
Q

MMF vs EC-MPS (Enteric Coated)
Maintenance Selection

A
  • NO DIFFERENCE IN:*
  • *Acute rejection** / pt or graft survival
  • *malignancy / infection / GI ADR**
  • some studies show:*
  • reduced* GI intolerance in EC-MPS > MMF
50
Q

When to use mTORi
instead of Antimetabolite (MPA>AZA)

A

Generally considered NOT suitable replacement for CNIs

Used as an alternative for
MPA intolerant patients w/ significant toxicities (intolerable)

Also for:
patients at risk for TUMOR RECURRENCE
or those with SKIN CANCERS

51
Q

What 2 drugs does CSA affect and HOW?
Drug Interactions

A

AZAthioprine
CSA –> *INHIBITS* enterohepatic reciculation
stops SECOND PEAK –> reduced AUC of AZA

Sirolimus / Everlimus
P-Gp substrate competition
VVV
INCREASED Sirolimus levels

Admin Sirolimus 4 hours after CSA

52
Q

Steroid Avoidance Considerations

A

Late Steroid Withdrawal:
High Incidence of Chronic Rejection
ADRs already manifesting

3-6months post-transplant
15-20% Acute Rejection / ↑CVD Risk

Early, 5-14 days post-txp
↑Acute Rejection
↓CVD Risk, long term graft fxn stays the same

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