Therapeutics II Exam 2 Transplant

MOA of Acute Cellular Rejection

T-cells infiltrate donor (allograft) via Endothelium

occurs first few months + any time

MOA of Abs Mediated Rejection

Abs against donor on endothelium activates complement → direct tissue dmg

first 3 months of TPx

Risks factors for organ rejection

Sensitized to more HLA agents (exposure to blood products, pregnancy, prior TPx)

Younger patients

African Americans

Deceased donors

Recent TPx

Med non-adherence

List induction IS meds

Alemtuzumab (Campath)

Rabbit Anti-Thymocyte Globulin (rATG)

Basiliximab (Simulect)

± Methylprednisolone

List Maintenance IS drugs + classes

Calcineurine inhibitors (Tacro + Cyclo)

Antimetabolites (Mycophenolic acid + Azathioprine)

mTORi (Everolimus, Sirolimus)

Co-stim blocker (Belatacept)

Corticosteroids (Prednisone)

What drug is classified as Lymphocyte Depleting Monoclonal Antibody

Alemtuzumab (Campath)

What drug is classified as Lymphocyte Depleting Polyclonal Antibody

Rabbit Anti-Thymocyte Globulin (rATG Thymoglobulin)

What drug is classified as Lymphocyte Non-depleting IL-2 Alpha RA

Basiliximab (Simulect)

Alemtuzumab MOA

Antibody against CD52 T & B Cell antigen → lysis

Duration of effects on B & T Cells by Alemtuzumab

3-12 months

2-3 years

Rabbit Thymoglobulin MOA

Binds to multiple lymphocyte receptors → complement-mediated Lysis and depletion

Alemtuzumab dosing

30mg IV once at time of TPx or in OR

Rabbit Thymoglobulin Dosing

4-7 mg/kg given as multiple doses

1-2 mg/kg/day

First dose in OR

What specific organ TPx is rATG most often used for as an induction agent

Kidney

Besides for Induction, what can rATG be used as

Rejection Treatment

What is the duration of effects does rATG has on T-cells

1 year

Basiliximab MOA

Chimeric monoclonal antibody that antagonized CD25 on active T-cells → prevents IL-2 mediated T-cell proliferation

Basiliximab Dosing

20 mg IV day 0 in OR and day 4 post TPx (2 drug regimen)

T/F: Basiliximab is associated with infusion reactions

False

What is the duration of effects does Basiliximab has on IL-2 saturation

4-6 weeks

Considerations when selecting an induction agent

High immunologic risk (autoimmune, prior TPx)

Advanced age

Hx of Malignancy (CA pt are not likely to be TPx pt)

Hx of significant infection

What maintenance drug classes require TDM

Calcineurine and mTOR inhibitors

List Calcineurin Inhibitors

Tacrolimus

Cyclosporin

List Antimetabolites

Azathioprine (Imuran)

Mycophenolate Mofetil (Cellcept)

Mycophenolic Sodium (Myfortic)

List mTOR inhibitors

Sirolimus (Rapamune)

Everolimus (Zortress)

List Selective T-cell costimulation blocker

Belatacept (Nulojix)

Of the 3 Signal Model of T-cell activation & proliferation, what signal does CNIs target

Signal 1

Of the 3 Signal Model of T-cell activation & proliferation, what signal does Selective T-cell costimulation blockers target

Signal 2

Of the 3 Signal Model of T-cell activation & proliferation, what signal does Antimetabolites target

Signal 3

Of the 3 Signal Model of T-cell activation & proliferation, what signal does mTOR inhibitors target

Signal 3

What is the estimate period of highest rejection risk post TPx

6 months - 1 year

Drugs that require TDM at 12 hour trough levels

Cyclosporin

IR Tacrolimus

Everolimus

Drugs that require TDM at 24 hour trough levels

ER Tacrolimus

Sirolimus

What drug classes make up the triple drug maintenance regimen

Calcineurin inhibitors

Antimetabolites

Corticosteroids

T/F: Tacrolimus is the preferred CNI

True

T/F: Azathioprine is the preferred Antimetabolite

False

T/F: IV Methylprednisolone can be used for induction

True

CNIs MOA

Bind to unique proteins on T-cells → inhibit Calcineurin from downstream T-cell activation

Tacrolimus IR ( Prograf) Dosing

0.1 - 0.3 mg/kg PO q12, then TDM

Tacrolimus ER (Envarsus CR) Dosing

0.14 mg/kg PO q24, then TDM

Tacrolimus ER (Astagraf XL) Dosing

0.15 - 0.2 mg/kg PO q24, then TDM

Prograf to Envarsus XR conversion

1 : 0.8

Prograf to Astagraf XL conversion

1:1

Prograf PO to Sublingual conversion

2:1

Prograf PO to IV (may be IVPG q12 or continuous infusion)

3-4 : 1

Cyclosporin Dosing

5-15 mg/kg/day q12, then titrated by TDM

Drugs that require TDM at 12 hour trough levels but 2 hours post-dose (C2) level or AUC monitoring is more accurate

Cyclosporin

Cyclosporin PO to IV conversion (may be IVPB q12 or continuous infusion)

3:1

T/F: Modified Cyclosporine is preferred due to better bioavailability

True

What main organ metabolized CNIs and may cause supratherapeutic drug levels if doses are not adjusted

Liver

African Americans have what enzyme that results in genetic rapid metabolism for CNIs

CYP3A5×1

T/F: CNIs have a common side effect of Tremors

True

Tacrolimus adverse drug effects

Nephrotoxicity

Neurotoxicity

Hyperglycemia

Alopecia

Diarrhea

Cyclosporine ADEs

Nephrotoxicity

HTN

Hyperlipidemia

Hyperuricemia

Hirsutism

Gingival hyperplasia

Azathioprine MOA

6-thioguanine metabolite into DNA → blocks purines synthesis → blocks cell proliferation

Disrupts de novo and salvage pathways

Mycophenolate MOA

Inhibits de novo purine synthesis in active T & B cells

Cannot use salvage pathway

Mycophenolate Mofetil (MMF) prodrug Dosing

1000 - 1500 mg PO q12

Mycophenolate Sodium (MPS) enteric coated Dosing

720 - 1080 mg PO q12

T/F: MMF must change to MPS when using IV route

False

MMF Cellcept to MPS Myfortic conversion

250 mg = 180 mg

Antimetabolite ADEs

N/V/D

Abdominal pain

Anemia

Leukopenia

Infection

Malignancy

What drug requires utilizing a REMS program to train prescribers, educate women on reproductive potential, and pregnancy registry

Mycophenolate (antimetabolites)

Mycophenolate patient education

Patients must used acceptable birth control during entire mycophenolate treatment and 6 months post cessation

• increased risk of miscarriage and birth defects

Pregnancy requires switching to Azathioprine

Mycophenolate Drug/Food interactions

Cyclosporine

Food

Aluminum Mg Antacids

Cholestyramine

Oral Fe

Pantoprazole

Antivirals

Azathioprine dosing

3-5 mg/kg PO SID

AZA PO to IV conversion

1:1

AZA ADEs

Dose limiting effects for Leukopenia, Anemia, Thrombocytopenia

N/V

Hepatotoxicity & Pancreatitis (reversible d/c dose)

Infections

Malignancy

AZA DDI with Xanthine Oxidase Inhibitors and MOA

Febuxostat & Allopurinol

Increased AZA & 6-P active metabolite concentrations → myelosuppression → myelotoxicity/leukopenia

IV Methylprednisolone Induction Dosing

250 - 1000 mg over a few days

PO Prednisone Dosing

Tapered off to lowest possible safe dose

PO Pred to IV Methylpred conversion

5:4

Corticosteroids DIs

Barbituates

Phenytoin

Rifampin induced hepatic metabolism of prednisolone to prednisone→ decreased effectiveness

Corticosteroids ADEs

Cataracts

Ulcers

Skin: striae, thinning, bruising, acne, fluid retention

HTN; Hirsutism; Hyperlipidemia

Infections

Necrosis

GI upset

Osteoporosis; Obesity

Insomnia; mood changes

DM

Corticosteroids monitoring

BP

BG

Lipid panel

DEXA scan

Eye exams

Why might CNIs be switched to or added to mTORi/Belatacept

Significant nephrotoxicity

New malignancy

Why might Antimetabolites be switched to or added to mTORi/Belatacept

GI intolerance to mycophenolate

What specific TPx might require mTORi or Belatacept alternative or adjunct

Liver TPx with Hx of Hepatocellular carcinoma

Heart TPx to prevent Cardiac Allograft Vasculopathy (CAV)

Sirolimus Dosing

6-10 mg PO initial dose

2-5 mg PO SID (t1/2 = 60 hours)

Everolimus dosing

0.75 - 2 mg PO q12 (t1/2 =6 t 18-35 hours

MTORi ADEs that results in avoided early post-TPx use

Dose related myelosuppression

Edema

Hypertriglyceridemia

Mouth ulcers

Anemia

Impaired wound healing

Hepatic artery thrombosis

Non-infectious pneumonitis

Belatacept dosing

De novo (immediately after TPx) 10 mg/kg

Switch to Belatacept: 5mg/kg

Q28 days once induction dosing complete

Interactions between mTORi and what other drug might increase mTORi levels

Cyclosporin

Separate by 4 hours or administer together

Belatacept BBW

Post-Transplant Lymphoproliferative Disorder (PTLD) with EBV Seronegative

Mild-Moderate Acute Cellular Rejection treatment

Optimize oral IS

Methylpred 250-1000 mg IV for 3-5 days followed by PO Pred taper

Mod-Severe Acute Cellular Rejection treatment

T-cell depleting therapy (Thymoglobulin or Azemtuzumab)

Antibody Mediated Rejection AMR Therapy

Steroids ± Rituximab ± IVIG ± Bortezomib ± Eculizumab ± Plasmapharesis

HTN Post-TPx Treatment that may be influenced by corticosteroids, CNIs, or impaired kidney graft function

Non-Dihydropyridine Ca++ Channel blockers (usually 1st line for CNI nephrotoxic effects)

Hyperlipidemia Post-TPx Treatment that may be influenced by corticosteroids, CNIs, or mTORi

Statins to reduce cardiac rejection and extend life

Statins should be avoided with what due to risk of Rhabdomyolosis

CNIs

DM Post-TPx treatment that may be influenced by Corticosteroids or CNIs

40% require Insulin

Preferred oral agent

SGLT2i for CV and renal benefits

Possible outcome when using SGLT2i in Kidney TPx

UTIs

Most common malignancy that occurs ~ 5 years post-TPx

Skin cancer

T/F: Tacrolimus and Cyclosporin are CYP3A4 substrates

True

Cyclosporin is metabolized by what enzyme

P-glycoprotein

CYP3A4 INHIBITORS that can INCREASE CNI levels

Grapefruit/Pomegranate

Protease inhibitors (HIV regimens, Paxlovid)

Azole antifungals

Cimetidine

Macrolides (except Azithromycin)

Amiodarone

Non-hydropyridine CCB (verapamil, diltiazem)

Tumeric / Green Tea

THC / CBD

CYP3A4 INDUCERS that could DECREASE CNI levels

Phenytoin

Phenobarbital

Carbamazepine

Rifampin / Rifabutin

St. John’s Wort

Agents that could increase nephrotoxicity with CNIs

ACEi/ARBs

Aminoglycosides

Amphotericin

NSAIDs

COX-2 inhibitors (Celebrex)