Down the Rabbit ... Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin...

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Transcript of Down the Rabbit ... Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin...

  • Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin

    Induction in High Risk Renal Transplant Recipients

    Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident

    University Health System Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

    Pharmacotherapy Education and Research Center University of Texas Health San Antonio

    August 14 and 18, 2017

    Learning Objectives: 1. Define acute rejection in renal transplant recipients 2. Describe induction therapy in renal transplantation 3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies

    in high risk renal transplant recipients 4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant

    recipients

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    Down the Rabbit Hole: Optimized Dosing for Rabbit Anti-Thymocyte Globulin Induction in High Risk

    Renal Transplant Recipients

    Elisabeth Kincaide, PharmD PGY2 Solid Organ Transplant Pharmacy Resident

    August 14 and 18, 2017 University Health System and McDermott Building

    Learning Objectives: At the completion of this activity, the participant will be able to:

    1. Define acute rejection in renal transplant recipients

    2. Describe induction therapy in renal transplantation

    3. Summarize the current literature for rabbit anti-thymocyte globulin induction dosing strategies in high risk renal transplant recipients

    4. Identify optimal rabbit anti-thymocyte globulin induction dosing in high risk renal transplant recipients

    Assessment Questions:

    1. All of the following are risk factors for acute rejection in renal transplantation, except: a. Advanced recipient age b. Elevated panel reactive antibody c. Extended criteria donor d. Repeat renal transplant

    2. Which agent is most efficacious for induction therapy in high-risk renal transplant recipients?

    a. Basiliximab b. Daclizumab c. Methylprednisolone d. Rabbit anti-thymocyte globulin

    3. Optimal induction dosing for rabbit anti-thymocyte globulin in high risk KTR may include:

    a. 1.5 mg/kg x 1 day b. 1.5 mg/kg x 3 days c. 15 mg/kg x 5 days d. 1.5 mg/kg x 14 days

    ***To obtain CE credit for attending this program please sign in. Attendees will be emailed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an email within 72 hours, please contact the CE Administrator at ana.franco-martinez@uhs-sa.com ***Faculty (Speaker) Disclosure: Elisabeth Kinciade has indicated she has no relevant financial relationships to disclose relative to the content of her presentation

    mailto:ana.franco-martinez@uhs-sa.com

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    I. Acute rejection in renal transplantation1,2 a. Cell mediated through alloreactive T-cells b. Typically occurs within 5 to 90 days after transplant, but can occur anytime

    II. Allorecognition1,2 a. Prime event which initiates immune response b. Recognition of antigens displayed by the transplanted organ

    III. T-cell activation1,2 a. APC activate T-cells through two signals

    i. Interaction between T-cell receptor and foreign antigens ii. Interaction between co-stimulatory receptors on the APC ligands and T-cells

    IV. Clonal expansion1,2 a. Under the influence of cytokines, activation leads to clonal expansion b. Antibodies will flag graft cells for destruction c. Endothelial damage and graft ischemia occurs

    V. Scientific Registry of Transplant recipients/Organ Procurement and Transplantation (SRTR/OPTN) acute rejection rates in adult kidney transplant recipients 12 mo. post transplantation3

    Acute Rejection

    Figure 1: Steps in acute rejection

    Figure 2: SRTR/OPTN Acute Rejection Rates

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    VI. Numerous risk factors for rejection have been identified3-5 a. Risk factors are not equivalent b. Criteria to meet “high risk” is extremely center-specific

    Table 1: Factors increasing risk for rejection

     Young recipient age

     Increased donor age

     African American recipients

     Repeat transplant

     Elevated PRA

     Multiple HLA mismatches

     DSA

     Positive cross match

     Blood group incompatibility

     Risk for DGF, i.e. prolonged ischemic time, DCD, ECD, obesity, high donor creatinine

    Refer to Appendix A for abbreviations

    I. Maintenance therapy

    a. Purpose: prevent acute and chronic rejection b. Combination therapy is used to target different steps of the immune cascade while

    minimizing drug-related toxicity II. Most common triple immunosuppression at the time of transplant includes the following3

    a. Tacrolimus: 95% b. Mycophenolate: 93% c. Corticosteroid: 70%

    I. Induction therapy1,4,5

    a. Purpose: provide a high level of immunosuppression when the risk of rejection is the highest

    b. Essential in patients at high risk for rejection II. KDIGO guidelines recommendations6

    a. Interleukin-2 receptor antagonist as first line i. Basiliximab

    b. Suggest a lymphocyte-depleting agent for high risk KTR i. rATG

    Maintenance Immunosuppression

    Induction Therapy in Renal Transplantation

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    III. Induction agents

    Figure 3: Immunosuppression therapy in KT

    IV. Immunosuppression a. Daclizumab and basiliximab are IL-2 receptor blockers

    i. Daclizumab was removed from the market in 2009 b. Campath® is no longer commercially available and can only be obtained through the U.S.

    Campath Distribution Program c. Anti-thymocyte globulin

    i. Atgam® equine formulation ii. Thymoglobulin® rabbit formulation

    V. OPTN/SRTR annual data report induction agent use in adult KTRs3

    Figure 4: OPTN/SRTR induction agent use

    Basiliximab (Simulect®)

    Daclizumab

    Lymphocyte depleting

    Non- lymphocyte

    depleting

    Alemtuzumab (Campath®)

    Anti-thymocyte globulin (equine

    and rabbit)

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    I. Description7

    a. Purified, pasteurized IgG obtained from immunizing rabbits with human thymocytes b. Serum is harvested and immunoglobulins are isolated c. Human red blood cells are used to deplete cross-reactive antibodies to non-T-cell antigens d. Exogenous viruses are removed

    II. Mechanism of action7 a. Polyclonal antibody b. Lymphocyte depletion by complement-dependent cell lysis c. Cytotoxic antibodies directed against antigens expressed on human T-lymphocytes d. Targets: CD2, CD3, CD4, CD8, CD25, CD45 e. Ultimate effect: lymphocytopenia in blood and T-cell depletion in spleen and lymph nodes f. Rapid and dose dependent T-cell depletion g. T-cell recovery: one year8,9

    III. Adverse events and warnings10 a. Anaphylaxis b. Central nervous system: chills, headache, fever, malaise, insomnia c. Cardiovascular: hypertension, peripheral edema, tachycardia, hypotension d. Respiratory: dyspnea, pulmonary disease e. Hematologic: leukopenia, thrombocytopenia, leukocytosis, anemia f. Immunosuppression: increased infection and malignancy risk

    i. Administer antibacterial, antifungal, and antiviral prophylaxis as clinically indicated g. Cytokine release syndrome

    i. Pre-medicate with corticosteroids, acetaminophen and/or antihistamine one hour prior to infusion

    IV. Monitoring7,10 a. CBC with deferential and platelet count b. Vital signs during administration c. Lymphocyte count monitoring is recommended

    i. Total lymphocyte and/or T-cell subsets, e.g. CD3 monitoring11-14

    V. rATG induction data in high risk KTR15,16

    Table 2: Trial summaries of rATG background literature

    Study Design N Intervention(s) MTN Result Safety

    Brennan (2006)15

    Prospective, Randomized

    1:1, open label, multi-

    center

    278

    rATG 1.5 mg/kg

    POD0-4 (7.5 mg/kg

    cumulative) vs. Bas 20 mg

    POD0 and 4

    CsA + MMF + steroids

    Treatment failure of rATG 25% vs. Bas

    38%, estimated group difference of -13% (95% CI: -24% to -2%); p=0.0202

    ↓BPAR in rATG

    cohort Bas (26%) vs. rATG

    (16%); p=0.02

     ↑ Infection in rATG group 86% vs. 75%; p=0.03

     ↑ leukopenia in rATG group 33% vs. 15%; p

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    Table 2: Trial summaries of rATG background literature

    Study Design N Intervention(s) MTN Result Safety

    Noel (2009)16

    Prospective, randomized

    230

    rATG 1.25 mg/kg POD0-7

    (10 mg/kg cumulative) vs. Dac 1 mg/kg x

    5 doses

    TAC + MMF+

    steroids

    Treatment failure of rATG 25% vs.

    Dac 34%, estimated group difference - 8% (95% CI: -20%

    to 4%)

    ↓BPAR in rATG cohort

    Dac (28%) vs. rATG (15%); p=0.016

     ↑ infections/pt in rATG group 2.5 vs. 1.8; p=0.014

     ↑CMV 19% rATG vs. 11% Dac (p=0.093)

     ↓ PLT, WBC and lymphocyte count in rATG arm at 1 wk; p

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    VIII. rATG induction dosing debate a. Initial dosing of rA