Solid Organ Transplantation and PK Immunosuppressants

Wynd

Kidney Transplantation

+potential reasons for tx, contraindications, organ source

• 80% of End Stage Renal Disease (ESRD) due to diabetes mellitus, hypertension, glomerulonephritis

• Contraindications to transplantation: unstable cardiac disease, newly diagnosed malignancy or conditions where risk of immunosuppression outweighs benefit

• Organ source: deceased (cadaveric) or living donors

Liver Transplantation

+potential reasons for tx, contraindications, organ source

• 60% of liver transplants due to noncholestatic cirrhosis (i.e., hepatitis B or C, alcoholic cirrhosis, cryptogenic cirrhosis, autoimmune hepatitis)

• Contraindications to transplantation: few, although retransplantation for hepatitis B or C is controversial

• Organ source: cadaveric (deceased) or living donors

Heart Transplantation

+potential reasons for tx, contraindications, organ source

• 90% of heart transplants due to idiopathic cardiomyopathy or ischemic heart disease

• Contraindications to transplantation: active infection, irreversible pulmonary hypertension, conditions that limit survival/ability for rehabilitation (e.g., malignancy)

• Organ source: cadaveric (deceased) donors

Class l Antigens

+locations, action page 12-13????

recognized by TCR → CD8+ marker on cytotoxic T cells

present in most nucleated cells & act as autorecognition of endogenously produced foreign substances like viral proteins or tumor antigens

Panel Reactive Antibody (PRA) or calculated PRA (cPRA)

+what is it, how are results reported, results + interpretation

marker of how sensitized a recipient is against potential donors

• in vitro

• blood sample tested against a spectrum of antigens representing a pool of potential donors

Results are reported as a percent → 0%-100%

• 0 = did NOT react against donors

• 100 = did react against all the potential donors

• >0% [cPRA ] = increased risk of rejection

• > 50% [cPRA ] = high immunologic risk

doesnt stop transplantation, immunosuppression may differ just individuals

Hyperacute Rejection

rare

occurs immediately (with minutes of reperfusion) due to donor-specific antibodies being present at time of transplant

Acute Cellular Rejection (ACR) def.

+timeline, tx approach

occurs most commonly within 1st year, but can occur at any point

Due to lymphocyte infiltration of graft with resultant cell death

Reversible within days if recognized and treated

• treatment is based on the severity of the rejection

“easier to treat”

Antibody mediated rejection (AMR) def.

+timeline, tx approach, who is at risk?

less common

difficult to treat

previously referred to as humoral (orvascular) rejection)

occurs within 1st 3 months ( but can occur later) due to HLA antigens being present in donor vascular endothelium

Highest risk among females, cytomegalovirus seropositive individuals and prior OKT3 exposure

treatment is based on the severity of the rejection

What is the major risk factor of ACR and AMR?

Nonadherence

Induction

+goal, time, common agents

Goal: massive immunosuppression to prevent acute rejection post- transplantation

Time in relation to transplantation: immediately prior to/during txp

Agents commonly used: monoclonal and polyclonal antibodies + corticosteroids

Tailor towards immunologic risk

Induction

+goal, time, common agents

Goal: maximize graft survival by suppressing immune response at several levels, thereby preventing acute rejection

Time in relation to transplantation: often within 24 hours of transplant. Duration controversial (usually “FOREVER”).

• Required in all cases except for identical twins (considered perfect matches)

iii. Agents commonly used:

calcineurin inhibitors (CNIs)

antimetabolites (MMF, MPA or AZA)

corticosteroids- may or not be used

mTOR inhibitors (sirolimus, everolimus)

costimulation blocker (belatacept) - Signal 2 pathway

Treatment of Rejection

+goal, time, common agents - ACR vs AMR

sometimes called “3rd phase”

i. Goal: acute cessation of rejection to maintain graft viability and function

ii. Time in relation to transplantation: during episode of acute rejection

iii. Agents commonly used (often in combination) → tailored towards severity and type of rejection

• Acute T-cell mediated rejection (ACR):

  • High dose corticosteroids +/-

  • Antibody therapy (polyclonal)

• Antibody mediated rejection (AMR) (directed towards antibody destruction, removal, and suppression, typically with multi-modal therapy):

  • High dose corticosteroids

  • Intravenous immunoglobulin (IVIG)

  • Plasmapheresis - physical removal of antibodies

  • Rituximab

  • Bortezomib

Immunosuppression Advantages vs disadvantages

Advantages

Decreases incidence of graft rejection

Disadvantages

• Increased vulnerability to opportunistic infection

• Increased incidence of malignancy

• Introduce side effects of the immunosuppressive agents

Cyclosporine (CsA)

+moa, place in treatment, administration, formulation considerations, IV conversion, therapeutic drug monitoring, bed dosing vs adults, ADEs, DDIs,

place in treatment: maintenance therapy (rarely used de novo)

• duration controversial, but typically “forever”

FYI moa: calcineurin inhibitior → decreases IL 2 → decreases T cell activation

considerations: ORAL CsA FORMULATIONS ARE NOT BIOEQUIVALENT!

• also avail IV

conversion: IV = 1/3 oral dose (TDD)

administration

• given BID

therapeutic drug monitoring

• trough concentrations - timed samples

• daily after initiation

AUC monitoring provides better predictive value but requires serial concentrations throughout the dosing interval to calculate accurately

3 options available: radioimmunoassay (RIA), fluorescence

polarization immunoassay and HPLC

Pediatrics often required higher doses due to increased drug clearance

ADEs:

• Nephrotoxicity

  • increased serum Cr and BUN, decreased GFR, hyperkalemia, high Na levels (decreased excretion), mild proteinuria

• Insulin dependent DM

DDIs: CYP 3A4 inhibitors or inducers; ex: HMG CoA reductase inhibitors

• St. John’s wort (enzyme inducer resulting in decreased CsA concentrations- and tacrolimus, and mTOR inhibitors)

• Grapefruit Juice

Avoid

High fat meals (enhance bioavailability and volume of distribution)

Live, attenuated vaccines may be less effective due to immunosuppression

avoid immunosuppressants that support immune system

Avoid cat’s claw or Echinacea due to immunostimulant properties

Sandimmune vs Neoral Absorption and Bioavailability

Sandimmune

• Olive oil based: dependent on bile

• Highly erratic in inter- and intra-patient

  variability with absorption

Neoral

• Non-bile dependent

• Absorbed faster, more consistently, and to a greater extent in comparison to Sandimmune capsules, oral solution (cyclosporine USP

bioavailability

• Sandimmune ≈ 30%

• Neoral 23-30% > Sandimmune

1:1 conversion Sandimmune® to Neoral → with close monitoring

Cyclosporine - DME

Distribution

• Volume of Distribution = 4 - 6 L/kg

• 90% protein bound

Metabolism - metabolites contribute to nephrotoxic and immunosppressive effects (not sure which ones)

Excretion

• Hemodialysis: not removed

Cyclosporine therapeutic concentration (Dont need to memorize? page 38, 40)

150 - 400 ng/mL

Taccrolimus

+formulations, dose conversion, administration, oral bioavailability, therapeutic drug monitoring, meds vs adult dosing, DDIs

place in therapy: Gold Standard

• maintenance

FYI moa: calcineurin inhibitior → decreases IL 2 → decreases T cell activation

• complexes with FK-binding protein 12 (not exactly same as cylcoporin)

formulations: oral - capsule, tablet, suspension, IV

• ER formulation across brand NOT interchangeable

conversion: IV - 1/5th the oral dose

• Increased frequency of TDM post-conversion recommended, target SDC is the same

• IV - more nephrotoxic than oral formulation

Administration

• once daily (ER)

• divided twice a day dosing (IR)

therapeutic Drug monitoring

• range varies by organ type and time from transplant

  among other factors

Pediatric doses = approximately twice adult dose

Oral Bioavailability

• 25%

  o Envarsus XR > Prograf, Astagraf

ADEs:

• Nephrotoxicity

• Insulin-dependent DM

• Emergent treatment of anaphylaxis (rare)

• malignancy

DDIs:

Interactions with medications that prolong the QTc-interval: tacrolimus > cyclosporine

CYP3A4 inhibitors - less reports of myopathy either HMG-CoA reductase administration

Avoid

High fat meals

grapefruit juice

Live, attenuated vaccines may be less effective due to immunosuppression

Avoid cat’s claw or Echinacea due to immunostimulant properties

St. John’s wort: enzyme induction may result in decreased tacrolimus concentrations

Tacrolimus DME

Distribution

• Vd = 1 (1 – 3) L/kg

• 99% plasma protein binding

metabolism

• substrate of CYP 3A4 - similar but not same as CSA

Excretion

• Urine: < 1 % of dose administered is excreted unchanged

  • not mechanism of nephrotox!

• • Hemodialysis: not removed

Mechanism of Nephortoxicity of CSIs

vasoconstriction of afferent arterial in the kidney (restrict blood flow to the kidney)

page 52?

Tacrolimus IR (Prograf) → ER (Astagraf)

Conversion— increased frequency of serum drug concentration therapeutic drug following conversion

Astagraf XL - Total daily dose administered ONCE daily

ex: Prograf (tacrolimus immediate-release) 5 mg PO q 12h → Astagraf XL (tacrolimus extended-release) 10 mg PO q 24h

Tacrolimus IR (Progrraf) → ER (Prograf)

Conversion—increased frequency of serum drug concentration therapeutic drug following conversion

Envarsus® XR ONCE-daily dose ≈ 80% of the total daily dose of the immediate-release

ex: Prograf (tacrolimus immediate-release) 5 mg PO q 12h → Envarsus XR (tacrolimus extended-release) 8 mg PO q 24h

CNIs: Balancing AEs and Efficacy

No method (other than completely avoiding CNIs) has been demonstrated superior to another at this time

Some strategies include:

1. Delaying CNI use (i.e., early avoidance strategy)

2. CNI therapeutic drug monitoring

3. Avoiding other nephrotoxins (e.g., NSAIDS, aminoglycosides)

4. Adjusting CNI doses based on anticipated changes in concentrations secondary to drug interactions

5. Decreasing and terminating use over time (i.e., withdrawal strategy)

6. True CNI avoidance strategies (e.g., de novo belatacept-based maintenance immunosuppression)

CNIs: Cyclosporine vs. Tacrolimus Summary on page 57

Tacrolimus is CNI of choice due to more predictable dose response & less patient intervariability, and lower rejection rate

nephrotoxicity is equal

Tacrolimus » hyperglycemia, neurotoxicity, GI tolerance, Alopecia

Cyclosporine » hyperlipidemia, hirsutism (hair growth)

Corticosteroids

+FYI moa, place in therapy, Clincial ADEs, DDIs,

FYI moa: nhibits cytokine production; Decreases number and functionality of circulating T lymphocytes

Palce in therapy:

Induction (high dose)

• Maintenance therapy (low doses for controversial duration)

• Rapid steroid withdrawal

• Steroid minimization

• Steroid avoidance

• High immunologic risk

ii. Treatment of rejection (pulse dosing)

Clinical ADEs:

• Metabolic: sodium and water retention, hyperglycemia/DM, appetite

• stimulation/weight gain, hyperlipidemia, osteoporosis

• CNS: euphoria → depression (symptom often dependent on dose)

• Cardiovascular: HTN, increased overall risk due to metabolic syndrome (HTN, glucose intolerance, hyperlipidemia)

• Decreased wound healing and increased risk infection

DDIs:

• MMF (Mycophenolate Mofetil): decreased MMF exposure due to steroid driven induction of uridine diphosphate

  glucuronosyltransferase, the enzyme responsible for MMF metabolism

  CNIs: increased concentrations with concomitant corticosteroid use due to CYP3A4 inhibition

  Increased corticosteroid clearance with concomitant phenytoin or phenobarbital

  Decreased antibody response with skin test antigens and live vaccines

Corticosteroids ADEs - Acute Vs Chronic

Acute

• Hyperglycemia

• Mental status changes

• Leukocytosis

Chronic

Clinical controversies of Corticosteroids

+strategeis to mimize exposure

Duration of use for maintenance therapy is generally minimized to off-set AEs

Use of steroids is guided by weighing the patients’ risk for corticosteroid-related AEs and benefits of their use

Patients at increased risk of AEs include postmenopausal women (osteoporosis), pediatrics (due to growth inhibition), prior history of malignancy, and significant cardiovascular risk factors such as pre-existing diabetes

Patients at increased risk of rejection (and therefore may be less likely to minimize steroids despite risks) include those of African American decent or those receiving poorly HLA matched organs

Current strategies to minimize steroid exposure focus on:

early steroid withdrawal (i.e., within 1 week of transplantation) or avoidance

late withdrawal of steroid (i.e., 3 to 6 months post-transplantation) has een associated with an increased incidence of acute rejection and is therefore not preferred