THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

20. Solid Organ Transplantation - Benjamin Duhart, Jr, MS, PharmD

20-1. Organ Transplantation

Principles of Transplantation

Types of allografts

• Heart: First successful transplant occurred in 1968. In 2007, 2,141 heart transplants were performed in the United States.

• Intestines: First successful transplant occurred in 1987. In 2007, 57 intestinal transplants were performed in the United States.

• Kidney: First successful cadaveric transplant occurred in 1954. In 2007, 16,119 kidney transplants were performed in the United States.

• Liver: First successful cadaveric transplant occurred in 1967. In 2007, 5,890 liver transplants were performed in the United States.

• Lung: First successful cadaveric single-lung transplant occurred in 1983. In 2007, 1,461 lung transplants were performed in the United States.

• Pancreas: First successful solitary pancreas transplant occurred in 1968. In 2007, 1,304 pancreas transplants were performed in the United States.

Goal

The goal is to improve patients' quality of life and survival by stabilizing and improving end-organ failure-related complications.

Patient and Graft Outcomes

Table 20-1 shows the patient and graft survival rates for transplant recipients.

Definitions

• Acute rejection: A systemic immunologic response to donor antigens primarily mediated by T-lymphocytes

• Adaptive immunity: Involves the stimulation of cells and soluble mediators in response to specific antigens with a markedly enhanced response on repeat exposure

• Complement: An enzyme system that is a crucial part of the basic immune response on primary exposure to an antigen and that also provides augmented signaling during memory immunity

• Human leukocyte antigen (HLA): Antigen-binding proteins that rescue protein fragments from intracellular catabolism (class I or II) or select antigens from the extracellular milieu that are then presented to lymphocytes (class II)

• Induction: Administration of short-term antibody therapy prior to and during the initial transplant as prophylaxis for acute rejection

• Innate immunity: Involves the stimulation of cells and soluble mediators that nonspecifically recognize antigens and have no ability to alter response with repeat exposure

• Major histocompatibility complex (MHC): A group of genes that encode for HLAs class I and II

• Opsonization: Occurs when antigens or immune complexes become coated with a molecule that facilitates binding with a phagocyte

• Panel reactive antibody (PRA): A test that quantifies a patient's immunologic reactivity to a given pool of antigens

• Phagocytosis: A process by which recognized antigens are engulfed and subsequently undergo intracellular catabolism

[Table 20-1. Kaplan-Meier Patient and Graft Survival Rates for Transplant Recipients]

Basic Immunology and Acute Rejection

Fundamental types of immunity

Innate immunity

Cellular components

• Macrophages: Phagocytic cells found throughout the body, which may function as antigen-presenting cells

• Neutrophils: Highly motile cells whose major physiologic role is the destruction of invading microorganisms through phagocytosis or opsonization

• Natural killer cells: A subset of non-B- and non-T-lymphocytes that survey for the normal biosynthesis and expression of HLA class I, making them important in immunity against viral infection and malignancy

Humoral components

• Complement: Activation leads to formation of lipophilic complexes, called membrane-attack complexes, in the cell membrane of the target cell and results in osmotic leakage.

• Physiologic function: Humoral component provides a defense against pyogenic bacterial infections.

• Bridges innate and adaptive immunity

• Mediates disposal of immune complexes

• Consists of acute phase proteins

Adaptive immunity

Cellular components

• Thymus-derived lymphocytes (T-cells): Mature T-cells become activated when they encounter an antigen-presenting cell (APC). T-cells do not recognize antigens directly.

• CD4+ T-cells (helper T-cells) recognize antigen presented via HLA class II.

• CD8+ T-cells (cytotoxic T-cells) recognize antigen presented via HLA class I.

• Bone marrow-derived lymphocytes (B-cells): B-cells encounter the antigen to which their surface immunoglobulin has specificity, through either its APC function or by interaction with an activated CD4+ T-cell. B-cell-CD4+ T-cell interaction is required for translocation into a follicle within secondary lymphoid tissue, where a germinal center forms and where high-affinity memory B-cells and plasma cells are produced and selected (somatic hypermutation).

Humoral components

• Complement: See the previous section on innate immunity.

• Immunoglobulin (Ig): This complex protein of various isotypes is formed as a consequence of B-cell activation for the purpose of binding and elimination of the activating antigen.

Acute rejection

Pathophysiology

During transplantation, the recipient is exposed to donor antigens to which he or she has no previous exposure. Although undesirable, acute rejection is the normal physiologic response of the immune system to these donor antigens. This response can be divided into five basic phases:

1. Recognition: Foreign antigen is recognized via self-or nonself-recognition mediated through MHC.

2. Presentation: On recognition, APC present antigens in association with native HLA class II to inactive CD4+ T-cells.

3. Activation and proliferation: Activation depends on antigen-HLA binding to the T-cell receptor (TCR) complex and the subsequent binding of a second signal or "co-stimulatory pathway." Subsequently, the active CD4+ T-cell produces and releases various lymphokines, particularly interleukin-2 (IL-2), which is important for activation and proliferation of numerous lymphocyte lineages.

4. Recruitment: Recruitment is mediated through several lymphokines produced as a consequence of lymphocyte activation.

5. Antigen and tissue destruction: Tissue injury is mediated through induction of polyclonal immune response.

Incidence

The incidence is organ specific and depends on many pre- and post-transplant factors. Several known factors increase risk:

• Increased HLA mismatch

• Factors affecting previous sensitization (e.g., history of pregnancy, previous transplantation, previous rejection, or panel reactive antibody > 20%)

• Ethnicity (i.e., African American recipients)

• Age (i.e., pediatric recipients)

• Donor source (i.e., cadaveric donor)

• Prolonged preservation time

• Noncompliance

Immunosuppressive Strategies

Balance of immunosuppression

Selection of an immunosuppression regimen for the prevention of acute rejection should be individualized on the basis of known risk and potential for toxicity. Subsequent adjustment must focus on the balance of the triad: rejection, infection, and toxicity.

Phases of preventive immunosuppression

Induction

The early phase is intended to provide highly potent, multifocal suppression of the immune system for several days to a few weeks. Commonly used agents include the following:

• Corticosteroids

• Monoclonal antibody (muromonab, basiliximab, daclizumab)

• Polyclonal antibody (antithymocyte globulin—equine or rabbit)

Maintenance

The immunosuppression regimen is designed to provide chronic, balanced immunodeficiency. Some commonly used regimens include the following:

• Double therapy:

• Calcineurin inhibitor + steroids

• Calcineurin inhibitor + antimetabolite

• Calcineurin inhibitor + mTOR (mammalian target of rapamycin) inhibitor

• mTOR inhibitor + steroids

• mTOR inhibitor + antimetabolite

• Antimetabolite + steroids

• Triple therapy:

• Calcineurin inhibitor + antimetabolite + steroids

• mTOR inhibitor + calcineurin inhibitor + steroids

• mTOR inhibitor + antimetabolite + steroids

Phases of immunosuppression during treatment

Treatment

Selection of the agents is organ specific and depends on the severity of acute rejection. Commonly used agents include the following:

• Corticosteroids

• Calcineurin inhibitor

• Tacrolimus may be used as the primary treatment of acute rejection in liver recipients.

• Tacrolimus may also have a role as adjuvant therapy in refractory acute rejection in various other solid organ recipients.

• Monoclonal antibody (muromonab)

• Polyclonal antibody (antithymocyte globulin—equine or rabbit)

Maintenance reevaluation

The decision to heighten maintenance immunosuppression depends on the cause for rejection (i.e., failure of regimen versus noncompliance).

Immunosuppressive Complications

Infectious

Infectious complications are an important cause of early morbidity and mortality. The incidence is organ specific and is closely linked to the net degree of immunodeficiency. Prevention is a key management strategy following transplantation. A list of infectious complications follows:

• Bacterial

• Tuberculosis: Mycobacterium tuberculosis

• Nocardiosis: Various species of Nocardia

• Fungal

• Aspergillosis: Various species of Aspergillus

• Blastomycosis: Blastomyces dermatitidis

• Candidiasis: Various species of Candida

• Coccidioidomycosis: Coccidioides immitis

• Cryptococcosis: Cryptococcus neoformans

• Histoplasmosis: Histoplasma capsulatum

• Mucormycosis: Various species of Mucor

• Pneumocystis pneumonia: Pneumocystis carinii (Pneumocystis jiroveci)

• Parasitic

• Toxoplasmosis: Toxoplasma gondii

• Viral

• Cytomegalovirus

• Epstein-Barr virus: including post-transplant lymphoproliferative disease

• Herpes simplex virus

• Varicella-zoster virus

• Human herpes viruses (i.e., HHV-6, HHV-8)

• Parvovirus

• Polyomavirus

Noninfectious

The noninfectious complications are specific to the agents included in the immunosuppressive regimen.

20-2. Immunosuppressants

Introduction

Immunosuppressant drugs are described in

Table 20-2.

Calcineurin Inhibitors

Cyclosporine

Mechanism of action

Cyclosporine inhibits calcineurin-dependent translocation of the cytosolic subunit of NFAT (nuclear factor of activated T-cells), the promoter gene for IL-2, into the nucleus, thereby inhibiting transcription and synthesis of IL-2; thus, it inhibits IL-2-mediated monoclonal T-cell proliferation and polyclonal T-cell activation.

Administration

• Intravenous

• Administer 5-6 mg/kg per day divided every 12 hours or as a continuous infusion. Each milliliter of IV concentrate should be diluted in 20-100 mL of normal saline (NS) or 5% dextrose in water (D5W) in a glass container. For bolus dosing, the dose should be infused over 2-6 hours.

• Oral

• Capsules: Administer the daily dose as two equally divided doses every 12 hours with meals.

• Oral solution: Administer the daily dose as two equally divided doses every 12 hours with meals. The solution may be diluted with chocolate milk or orange juice in a glass container. Additional diluent should be used to rinse the container to ensure administration of the total dose.

Drug-drug interactions

The drug is metabolized primarily via cytochrome P450 (CYP450) 3A isoenzymes. Substances known to alter functionality of these enzymes will alter bioavailability and elimination of this drug (

Table 20-3).

Drug interactions lead to altered exposure of other drugs by cyclosporine (

Table 20-4).

Drug-disease interactions

• Altered biliary flow: Diversion of biliary flow can significantly reduce adsorption. This more profoundly affects cyclosporine USP (United States Pharmacopeia) than it does cyclosporine USP (modified).

• Diabetes mellitus: Administration worsens glycemic control in patients with preexisting diabetes.

• Vaccination: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• Central nervous system (CNS): Seizure, hallucinations, insomnia, tremor, paresthesias

• Head, ears, eyes, nose, and throat (HEENT): Gingival hyperplasia

• Cardiovascular (CV): Hypertension

• Gastrointestinal (GI): Hepatotoxicity

• Renal: Nephrotoxicity

• Endocrine and metabolic: Diabetes mellitus, hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia

• Dermatologic: Hirsutism, hypertrichosis, acne

[Table 20-2. Immunosuppressant Drugs]

[Table 20-3. Drug Interactions Leading to Altered Exposure of CYP450 3A Isoenzyme Substrates]

Patient instructions

• Keep cyclosporine stored in its original container.

• Take the prescribed dose twice daily with meals.

• Keep timing of dosing consistent.

• Make sure you take or do not take your medication at the appropriate time prior to therapeutic drug monitoring.

• Many medications interact with this medication. Do not take anything prescribed by another physician until you verify that there are no drug interactions.

Monitoring

• C0 (trough): Goals depend on multifactorial risk assessment and assay type.

• C2 (concentration 2 hours after dose): Goals depend on multifactorial risk assessment and assay type.

Pharmacokinetics

• Cyclosporine USP: Highly lipoprotein bound

• Bioavailability: significant intra- and interpatient variability

[Table 20-4. Drug Interactions Leading to Altered Exposure of Other Drugs by Cyclosporine]

• Mean F = 30%, range 5% to 92%

• Elimination: half-life = 19 hours; range 10-28 hours (increased with hepatic dysfunction)

• Cyclosporine USP (modified): Highly lipoprotein bound

• Bioavailability: improved and more consistent absorption (60-70% increased Cmax)

• Elimination: half-life = 8 hours; range 5-18 hours (increased with hepatic dysfunction)

Tacrolimus

Mechanism of action

Tacrolimus inhibits translocation of the cytosolic subunit of NFAT, the promoter gene for IL-2, into the nucleus via its binding with FKBP-12 and a calcium-calmodulin-calcineurin complex, thereby inhibiting transcription and synthesis of IL-2. Thus, it inhibits IL-2-mediated monoclonal T-cell proliferation and polyclonal T-cell activation.

Administration

• Intravenous: Dilute in NS or D5W to a concentration between 0.004 and 0.02 mg/mL, and administer as a continuous infusion via a PVC (polyvinylchloride)-free container and tubing.

• Oral: Administer two equally divided doses po every 12 hours consistently, with or without food.

Drug-drug interactions

Because tacrolimus is metabolized primarily via CYP450 3A isoenzymes, substances known to alter functionality of these enzymes will alter bioavailability and elimination of this drug (Table 20-3).

Drug-disease interactions

• Diabetes mellitus: Administration worsens glycemic control in patients with preexisting diabetes.

• Vaccinations: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• CNS: Seizure, hallucinations, insomnia, tremor, depression, psychosis, anorexia

• HEENT: Alopecia

• CV: Hypertension

• GI: Hepatotoxicity

• Renal: Nephrotoxicity

• Endocrine and metabolic: Diabetes mellitus, hyperlipidemia, hyperkalemia, hypercalcemia, hypomagnesemia, hypophosphatemia

• Hematologic: Anemia

Patient instructions

• Take the prescribed dose at a consistent time twice daily, with or without food, but always in the same way to maintain consistency.

• Make sure you do not take your medication prior to therapeutic drug monitoring.

• Many medications interact with this medication. Do not take anything prescribed by another physician until you verify that there are no drug interactions.

Monitoring

Monitor C0 (trough). Goals depend on multifactorial risk assessment (in general, 5-20 ng/mL).

Pharmacokinetics

• Highly protein bound

• Bioavailability: F = 14-32%

• Elimination: half-life = 8 hours; range 6-11 hours (increased with hepatic dysfunction)

mTOR Inhibitor

Sirolimus

Mechanism of action

Sirolimus binds to FKBP-12 to form a complex that binds and inhibits activation of its target protein, mTOR (mammalian target of rapamycin), a kinase that is critical in IL-2-mediated cell-cycle progression.

Administration

• To limit variability, administer consistently with or without food.

• With tablets, administer daily dose po once a day.

• With oral solution, dilute the dose in 2 oz of water or orange juice, stir vigorously, and drink at once. Then refill container with 4 oz of the chosen fluid, stir vigorously, and drink.

Drug-drug interactions

Because sirolimus is metabolized primarily via CYP450 3A isoenzymes, substances known to alter functionality of these enzymes will alter bioavailability and elimination of this drug (Table 20-3).

Additionally, the pharmacokinetic profile of sirolimus is significantly altered by concomitant cyclosporine (Table 20-4).

Drug-disease interactions

• Liver transplantation: Sirolimus is associated with increased incidence of mortality, graft loss, and hepatic artery thrombosis in de novo liver transplant recipients.

• Lung transplantation: There have been cases of fatal bronchial anastomotic dehiscence in de novo lung transplant recipients.

• Vaccinations: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• CNS: Anorexia

• HEENT: Oral ulcers

• GI: Diarrhea, esophagitis, gastritis, gastroenteritis, hepatotoxicity, hepatic artery thrombosis in de novo liver transplant recipients

• Renal: Synergistic nephrotoxicity with calcineurin inhibitors

• Endocrine and metabolic: Hyperlipidemia, hypertension, hyperkalemia

• Dermatologic: Rash, acne

• Hematologic: Leukopenia, thrombocytopenia, pancytopenia, thrombosis

• Other: Lymphocele, pneumonitis, bronchial anastomotic dehiscence in de novo lung transplant recipients

Patient instructions

• Take the prescribed dose at a consistent time once daily, with or without food, but in the same way to maintain consistency.

• Make sure you do not take your medication prior to therapeutic drug monitoring.

• Many medications interact with this medication. Do not take anything prescribed by another physician until you verify that there are no drug interactions.

Monitoring

Monitor C0 (trough). Goal depends on multifactorial risk assessment and assay type (in general, 5-20 ng/mL).

Pharmacokinetics

• Bioavailability: tablet: F = 27%; oral solution: F = 15%

• Elimination: half-life = 57-63 hours (increased with hepatic dysfunction)

Antiproliferative Agents

Azathioprine

Mechanism of action

Azathioprine is a purine analogue prodrug, which is cleaved to 6-mercaptopurine; 6-mercaptopurine is activated intracellularly to several active metabolites, which can be incorporated directly into DNA (deoxyribonucleic acid) as thiopurine as well as interfere with the RNA (ribonucleic acid) and DNA biosynthesis directly and via feedback inhibition.

Administration

• Intravenous: Dilute dose in NS or D5W and administer IV infusion over 5-60 minutes.

• Oral: Administer daily dose po once a day.

Drug-drug interactions

Xanthine oxidase is responsible for the elimination of the active metabolites of azathioprine. Concomitant use of allopurinol with azathioprine results in significantly increased azathioprine-induced toxicity. Reduce dose of azathioprine by 65-75%.

Drug-disease interactions

• Renal insufficiency: Bioavailability is significantly reduced in uremic patients.

• Vaccinations: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• HEENT: Retinopathy

• GI: Nausea, vomiting, diarrhea, anorexia, pancreatitis, hepatotoxicity

• Dermatologic: Rash, skin cancer

• Hematologic: Leukopenia, thrombocytopenia, pancytopenia

Patient instructions

• Take the prescribed dose at a consistent time once daily, with or without food, but take in the same way to maintain consistency.

• Do not take anything prescribed by another physician until you verify that there are no drug interactions.

Monitoring

No clinically important pharmacokinetic or pharmacodynamic monitoring exists.

Pharmacokinetics

• Bioavailability: F = 41-47%

• Bioavailability in uremic patients: F = 17%

Mycophenolate mofetil

Mechanism of action

Mycophenolate mofetil is metabolized to mycophenolic acid (MPA), which causes noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a critical enzyme in the de novo pathway of purine synthesis, which is crucial during lymphocyte activation and proliferation.

Administration

• Intravenous: Dilute in D5W to a concentration of 6 mg/mL and infuse over at least 2 hours.

• Oral: Administer as equally divided doses po every 8-12 h consistently with or without food.

Drug-drug interactions

• Cyclosporine: See Table 20-4.

• Cholestyramine: Because of the interruption of enterohepatic recirculation, administration can decrease MPA exposure.

• Colestipol and colesevelam: Simultaneous administration can decrease MPA exposure.

• Antacids: Simultaneous administration with magnesium- or aluminum-containing antacids reduces absorption and decreases MPA exposure.

• Note: Efficacy of oral contraceptives may decrease with therapy. Additional birth control methods are recommended.

Drug-disease interactions

• Severe renal impairment: Mycophenolate mofetil reduces protein binding of MPA.

• Vaccinations: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• GI: Nausea, vomiting, diarrhea, abdominal pain

• Hematologic: Leukopenia, thrombocytopenia, anemia, pancytopenia

Patient instructions

• Take the prescribed dose at consistent times during the day, with or without food, but in the same way to maintain consistency.

• Make sure you do not take your medication prior to therapeutic drug monitoring.

Monitoring

No clinically important pharmacokinetic or pharmacodynamic monitoring exists.

Pharmacokinetics

• MPA is highly protein bound.

• Bioavailability: F = 94%

• Elimination: half-life = 16-18 hours

Mycophenolate sodium

Mechanism of action

Delayed-release tablets deliver MPA, which causes noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a critical enzyme in the de novo pathway of purine synthesis, which is crucial during lymphocyte activation and proliferation.

Administration

Administer as equally divided doses po every 12 hours consistently without food.

Drug-drug interactions

• Cholestyramine: Administration interrupts enterohepatic recirculation and decreases MPA exposure.

• Antacids: Simultaneous administration with magnesium- or aluminum-containing antacids reduces absorption and decreases MPA exposure.

• Note: Efficacy of oral contraceptives may decrease with therapy. Additional birth control methods are recommended.

Drug-disease interactions

• Severe renal impairment: Mycophenolate sodium reduces protein binding of MPA.

• Vaccinations: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• GI: Nausea, vomiting, diarrhea, abdominal pain

• Hematologic: Leukopenia, thrombocytopenia, anemia, pancytopenia

Patient instructions

• Take the prescribed dose at consistent times during the day, either 30 minutes before or 2 hours after meals, but take the same way each day to maintain consistency.

• Make sure you do not take your medication prior to therapeutic drug monitoring.

Monitoring

No clinically important pharmacokinetic or pharmacodynamic monitoring exists.

Pharmacokinetics

• MPA is highly protein bound.

• Bioavailability: F = 72% to 92%

• Elimination: half-life = 8-16 hours

Corticosteroids

Selection of agent

Selection of the corticosteroid used is based on the ratio of glucocorticoid to mineralocorticoid potency.

Intravenous agents are methylprednisolone and dexamethasone. Oral agents are prednisone, prednisolone, and dexamethasone.

Mechanism of action

Corticosteroids bind to cytosolic glucocorticoid receptors, which translocate to the nucleus, where the complexes bind to regulatory DNA sequences, glucocorticoid-responsive elements (GREs) within the promoter section of various genes. Activation of these GREs modifies activities of promoter genes such as NFAT, AP-1, and NF-κB, which results in downregulation of expression of HLA and numerous cell adhesion molecules, as well as decreased synthesis of numerous lymphokines responsible for activation, proliferation, and migration (i.e., IL-1, IL-2, IL-6, IL-8, IFN-γ, TNF-α).

Administration

Administration depends on the individual agent.

Drug-drug interactions

Because corticosteroids are metabolized primarily via CYP450 3A isoenzymes, substances known to alter functionality of these enzymes will alter bioavailability and elimination of these drugs (Table 20-3).

Drug-disease interactions

• Diabetes mellitus: Administration worsens glycemic control in patients with preexisting diabetes.

• Osteopenia and osteoporosis: Administration alters calcium and phosphate absorption and excretion, as well as osteoblast activity, resulting in progression of bone loss that is common in metabolic diseases such as end-stage renal disease and liver failure.

• Vaccinations: In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

The incidence and extent of most adverse drug reactions with corticosteroids depend on the ratio of glucocorticoid to mineralocorticoid potency. Adverse drug events include the following:

• CNS: Seizure, psychosis, delirium, hallucinations, mood swings, insomnia, pseudotumor cerebri

• HEENT: Cataracts, glaucoma

• CV: Hypertension, cardiomyopathy

• GI: Increased appetite, gastroesophageal reflux disease, peptic ulcer disease, pancreatitis

• Renal: Edema, alkalosis, hyperkalemia

• Endocrine and metabolic: Diabetes mellitus, hyperlipidemia, hypothalamic-pituitary-adrenal axis suppression, growth suppression

• Dermatologic: Hirsutism, acne, skin atrophy, impaired wound healing

• Hematologic: Transient leukocytosis

• Musculoskeletal: Arthralgia, myopathy, osteoporosis, avascular necrosis

Patient instructions

• When taking orally, take daily dose in the morning with food.

• Many drugs interact with these agents. Do not take anything prescribed by another physician until you verify that there are no drug interactions.

Monitoring

No clinically important pharmacokinetic or pharmacodynamic monitoring exists.

Pharmacokinetics

Pharmacokinetics depend on the individual agent.

Monoclonal Antibodies

Orthoclone OKT3

Mechanism of action

Murine monoclonal IgG binds to and facilitates removal of cell lines expressing CD3. CD3, part of the T-cell receptor complex, is an important molecule that distinguishes T-cells. CD3 is important in antigen recognition and antigen-specific signal transduction.

Administration

• Premedication:

• Dose 1: Intravenous steroids, acetaminophen, and antihistamines taken 1 hour prior to the dose are strongly recommended to modify first-dose reactions.

• Subsequent doses: Take acetaminophen and antihistamines 1 hour prior to the dose with steroids as needed for infusion-related reactions.

• Dosing:

• Prior to administration, volume status must be carefully assessed.

• Patients with evidence of volume overload or uncompensated congestive heart failure on chest x-ray should not receive this drug.

• The dose should be administered via IV bolus over less than a minute.

Drug-drug interactions

No clinically significant interactions occur.

Drug-disease interactions

• Uncompensated congestive heart failure or volume overload presents risk of fatal pulmonary edema.

• In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

• CNS: Dizziness, headache

• HEENT: Photophobia

• CV: Tachycardia

• Hematologic: Transient lymphopenia, pancytopenia

• Musculoskeletal: Rigor, tremor

• Other: Fever, chills, dyspnea, pulmonary edema

Patient instructions

Report any shortness of breath, palpitations, light-headedness, tremor, fever, or itching to your medical care provider immediately.

Monitoring

Monitor CD3 (suppression of CD3 lineage < 25 cells/mm3).

Pharmacokinetics

Elimination: half-life = 18 hours

Basiliximab

Mechanism of action

Chimeric (murine and human), monoclonal IgG specifically binds to the subunit, CD25, of the human high-affinity IL-2 receptor, which is expressed only on activated lymphocytes. In this way, basiliximab competitively inhibits IL-2 and facilitates preferential elimination of activated lymphocytes.

Administration

Dilute to a concentration of 0.4 mg/mL in NS or D5W. Administer peripherally or centrally as a bolus or continuous infusion over 20-30 minutes.

Drug-drug interactions

No clinically significant drug interactions occur.

Drug-disease interactions

In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

Severe acute hypersensitivity reactions, including anaphylaxis, may occur within the 24 hours following administration of the initial dose or on repeat exposure.

Patient instructions

Report any shortness of breath, palpitations, light-headedness, or itching to your medical care provider immediately.

Monitoring

No clinically important pharmacokinetic or pharmacodynamic monitoring exists.

Pharmacokinetics

• Adults (following a 20 mg IV infusion over 20 minutes):

• Mean Cmax = 7.1 ± 5.1 mg/L

• Mean half-life = 7.2 ± 3.2 days

• Children: Mean half-life = 11.5 ± 6.3 days

Pharmacodynamics

• Adults: CD25 saturation is at or above serum concentration of 0.2 mcg/mL. Mean duration of saturation depends on concomitant immunosuppressive regimen.

• Children: CD25 saturation is similar to that seen in adults.

Daclizumab

Mechanism of action

Humanized monoclonal IgG specifically binds to the subunit, CD25, of the human high-affinity IL-2 receptor, which is expressed only on activated lymphocytes. In this way, daclizumab competitively inhibits IL-2 and facilitates preferential elimination of activated lymphocytes.

Administration

Dilute in 50 mL of NS and administer peripherally or centrally as a continuous infusion over 15 minutes.

Drug-drug interactions

No clinically significant drug interactions occur.

Drug-disease interactions

In general, immunosuppressants may affect efficacy of vaccination. The use of live vaccines should be avoided.

Adverse drug reactions

Severe acute hypersensitivity reactions, including anaphylaxis, have rarely occurred within the 24 hours following administration of the initial dose or on repeat exposure.

Patient instructions

Report any shortness of breath, palpitations, light-headedness, or itching to your medical care provider immediately.

Monitoring

No clinically important pharmacokinetic or pharmacodynamic monitoring exists.

Pharmacokinetics

• Adults (at recommended dosing):

• Mean Cmax: dose 1 = 21 ± 14 mg/mL; dose 5 = 32 ± 22 mg/mL

• Mean Cmin: dose 5 = 7.6 ± 4.0 mg/mL

• Half-life = 20 days

• Children (at recommended dosing):

• Mean Cmax: dose 1 = 16 ± 12 mg/mL; dose 5 = 21 ± 14 mg/mL

• Mean Cmin: dose 5 = 5.0 ± 2.7 mg/mL

• Half-life = 13 days

Pharmacodynamics

• Adults: CD25 saturation is at serum concentrations of 5-10 mg/mL. At recommended dosing, saturation occurs for approximately 120 days.

• Children: CD25 saturation is at serum concentrations of 5-10 mg/mL. At recommended dosing, saturation occurs for approximately 90 days.

Polyclonal Antibodies

Antithymocyte globulin (equine)

Mechanism of action

This antithymocyte globulin is purified, sterile, polyclonal IgG harvested from horses immunized with human thymocytes. The preparation includes IgG directed against cell surface markers such as CD2, CD3, CD4, CD8, CD11a, and CD 18. In this way, horse antithymocyte globulin targets multiple phases of immunity, including T-cell activation, homing, and cytotoxic activities.

Administration

• Premedication:

• Dose 1: Giving intravenous steroids, acetaminophen, and antihistamines 1 hour prior to the dose is strongly recommended to modify first-dose reactions.

• Subsequent doses: Give acetaminophen and antihistamines 1 hour prior to the dose with steroids as needed for infusion reactions.

• Dosing:

• Dilute the dose to a concentration not to exceed 4 mg/mL in 1/2NS or D5W.

• Administer centrally over 4-6 hours.

Drug-drug interactions

No clinically significant drug interactions occur.

Drug-disease interactions

In general, immunosuppressants may affect the efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

Most adverse drug reactions with antithymocyte globulin (equine) are infusion-related reactions (i.e., fever, chills, and dyspnea); leukopenia; thrombocytopenia; or rash.

Patient instructions

Report any shortness of breath, palpitations, light-headedness, tremor, fever, or itching to your medical care provider immediately.

Monitoring

The goal for treatment of acute rejection is suppression of CD3 lineage to <50 cells/mm3.

Pharmacokinetics

Elimination: half-life = 36 hours-12 days

Antithymocyte globulin (rabbit)

Mechanism of action

This antithymocyte globulin is purified, pasteurized, polyclonal IgG harvested from pathogen-free rabbits immunized with human thymocytes. This preparation includes IgG directed against cell surface markers, such as TCRab, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a, CD18, CD28, CD45, CD49, CD54, CD58, CD80, CD86, HLA class I, and β2 microglobulin. In this way, rabbit antithymocyte globulin targets multiple phases of immunity, including T-cell activation, homing, and cytotoxic activities.

Administration

• Premedication:

• Dose 1: Giving intravenous steroids, acetaminophen, and antihistamines 1 hour prior to the dose is strongly recommended to modify first-dose reactions.

• Subsequent doses: Give acetaminophen and antihistamines 1 hour prior to the dose with steroids as needed for infusion reactions.

• Dose:

• Dilute dose to a concentration of 0.5 mg/mL in NS or D5W.

• Administer centrally over 4-6 hours.

Drug-drug interactions

In the case of immunoglobulin, administration may decrease the degree of lymphocyte depletion achieved.

Drug-disease interactions

In general, immunosuppressants may affect efficacy of vaccinations. The use of live vaccines should be avoided.

Adverse drug reactions

Most adverse drug reactions with antithymocyte globulin (rabbit) are infusion-related reactions (i.e., fever, chills, and dyspnea); leukopenia; thrombocytopenia; or rash.

Patient instructions

Report any shortness of breath, palpitations, light-headedness, tremor, fever, or itching to your medical care provider immediately.

Monitoring

The goal for treatment of acute rejection is suppression of CD3 lineage to < 50 cells/mm3.

Pharmacokinetics

A two-compartment model is used. For terminal elimination, half-life = 2-3 days for first dose; range = 14-45 days with multiple doses.

20-3. Key Points

• The goal of solid organ transplantation is to improve patients' quality of life and survival by stabilizing or improving complications related to end-organ failure.

• The immune system is a highly intricate system with mechanisms for antigen recognition in a highly specific manner, as well as in a nonspecific manner.

• Acute rejection is a normal physiologic immune response to transplantation of donor antigens.

• The incidence of acute rejection is organ specific and depends on multiple pre- and post-transplant factors.

• Selection of the post-transplant immunosuppression regimen for prevention of acute rejection should be individualized on the basis of known risk and potential toxicity.

• Adjustment in the post-transplant immunosuppression regimen should focus on the balance between acute rejection, infection, and toxicity.

• Selection of the agent to be used to treat acute rejection is organ dependent and depends on the severity of acute rejection.

• Immunosuppressive complications, both infectious and noninfectious, are an important cause of early morbidity and mortality and require close management following transplantation.

• Many agents commonly included in immunosuppression regimens require a clinician with expertise in immunosuppressive therapeutic drug monitoring to optimize efficacy and reduce toxicity.

• Many agents commonly included in immunosuppression regimens have the potential for numerous pharmacokinetic and pharmacodynamic drug interactions.

20-4. Questions

Use Patient Profile 1 to answer questions 1-4.

 

Patient name: Doe, John

Age: 52

Gender: Male

Ethnicity: African American

Diagnoses:

h/o ESRD s/p cadaveric renal transplant 3 mo ago

DM × 20 yrs

HTN × 30 yrs

Drug-induced hyperkalemia

Current laboratory results:

SCr = 1.2

K = 5.3

WBC 3.8

Plt 120

Address: 101 South First Street

Height: 5´11″

Weight: 240 lb

Allergies: Sulfa

Medications prior to hospital admission:

Prograf 4 mg po bid

Amaryl 4 mg po bid

Cellcept 750 mg po bid

Metoprolol 100 mg po bid

Diflucan 200 mg po qd

Dapsone 100 mg po qd

Valcyte 450 mg po qd

EC ASA 81 mg po qd

Prednisone 5 mg po qd


Additional medications prescribed during hospital course:

Lasix 40 mg po bid

Imuran 100 mg po qd

1.

Which medication(s) should be given with caution because of the patient's sulfonamide allergy?

I. Lasix

II. Dapsone

III. Amaryl

A. I only

B. II only

C. I and III only

D. II and III only

E. I, II, and III

 

2.

Which of the following combinations of drugs represent therapeutic duplication?

A. Prograf and Imuran

B. Azathioprine and CellCept

C. Dapsone and Valcyte

D. Amaryl and Tacrolimus

E. Prednisone and CellCept

 

3.

Which of the following combinations of drugs interact?

I. Diflucan and tacrolimus

II. Diflucan and Valcyte

III. Dapsone and Lasix

A. I only

B. II only

C. I and II only

D. II and III only

E. I, II, and III

 

4.

Mr. Doe was diagnosed with drug-induced hyperkalemia. Which medication on his profile could be responsible for this?

A. CellCept

B. Lasix

C. Prednisone

D. Prograf

E. EC ASA

 

5.

Which medication(s) is (are) classified as a calcineurin inhibitor?

I. Rapamune

II. Cyclosporine

III. Tacrolimus

A. I only

B. II only

C. III only

D. II and III

E. I and III

 

6.

Which medication(s) cause myelosuppression?

I. Sirolimus

II. Mycophenolate mofetil

III. Valcyte

A. I only

B. II only

C. III only

D. I, II, and III

E. II and III

 

7.

Which medication(s) require bile for emulsification and absorption?

A. Imuran

B. Cyclosporine

C. Prograf

D. Prednisone

E. All of the above

 

8.

All of the following are known adverse effects of cyclosporine except

A. hirsutism.

B. nephrotoxicity.

C. oral ulceration.

D. gingival hyperplasia.

E. hyperlipidemia.

 

9.

All of the following are contraindications or precautions associated with Rapamune except

A. de novo lung transplant recipient.

B. hyperlipidemia.

C. diabetes mellitus.

D. de novo liver transplant recipient.

E. allergy to sirolimus.

 

10.

What is the generic name for Imuran?

A. Mycophenolate mofetil

B. Azathioprine

C. Cyclosporine

D. Tacrolimus

E. Prednisone

 

11.

Which of the immunosuppressive medication(s) listed may cause diabetes mellitus?

I. Prednisone

II. Azathioprine

III. Tacrolimus

A. I only

B. II only

C. III only

D. I and III

E. I, II, and III

 

12.

Which medication(s) require(s) therapeutic drug monitoring via trough concentrations?

A. Mycophenolate mofetil

B. Prograf

C. Daclizumab

D. Basiliximab

E. Mycophenolate mofetil and Prograf

 

13.

Which medication(s) select(s) for destruction of activated lymphocytes by binding to the CD25 subunit of the high affinity IL-2 receptor?

I. Antithymocyte globulin (rabbit)

II. Antithymocyte globulin (equine)

III. Daclizumab

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

14.

All of the following increase the risk of acute rejection except

A. pediatric recipient.

B. HLA mismatch.

C. living donor.

D. noncompliance.

E. history of previous transplantation.

 

15.

Which of the following produces a significant pharmacokinetic interaction when administered with azathioprine?

A. Allopurinol

B. Diflucan

C. Sirolimus

D. Probenecid

E. Allopurinol and probenecid

 

16.

Which of these conditions alter(s) the pharmacokinetic profile of cyclosporine?

I. Biliary obstruction

II. Malnutrition

III. Hyperglycemia

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

17.

Which of the following medication(s) interact(s) with sirolimus?

I. Erythromycin

II. Prevalite

III. Diltiazem

A. I only

B. II only

C. III only

D. I and III

E. II and III

 

18.

Which of the following immunosuppressants should not be administered at the same time secondary to an interaction related to timing of doses?

I. Prograf and mycophenolate mofetil

II. Rapamune and cyclosporine

III. Neoral and azathioprine

A. I only

B. II only

C. III only

D. None of these interact.

E. II and III

 

19.

Which type of immunity involves stimulation of cells and soluble mediators that nonspecifically recognize alloantigens with no altered response on repeat exposure?

A. Autoimmunity

B. Innate immunity

C. Adaptive immunity

D. Acute rejection

E. Hyperacute rejection

 

20.

Which group of genes encodes for antigens that are responsible for self- or nonself-recognition?

I. Class I human leukocyte antigen (HLA)

II. Class II human leukocyte antigen (HLA)

III. Major histocompatibility complex (MHC)

A. I only

B. II only

C. III only

D. I and II

E. I, II, and III

 

21.

On binding of antigen displayed by the antigen-presenting cell to the T-cell receptor complex, what additional step is required for T-helper-cell activation?

I. Binding of the co-stimulatory pathway (i.e., CD58/CD2)

II. Activation of the promoter gene NFAT

III. Transcription of the IL-2 gene

A. I only

B. II only

C. III only

D. No additional step is required.

E. I and II

 

22.

Which cytokine released by activated CD4+ lymphocytes plays a major role in the subsequent activation of numerous lymphocyte lineages?

A. Interleukin-1 (IL-1)

B. Tumor necrosis factor-α (TNF-α)

C. Interleukin-2 (IL-2)

D. Interferon-γ (IFN-γ)

E. Complement

 

23.

Which solid organ was the first to be successfully transplanted?

A. Heart

B. Liver

C. Kidney

D. Lung

E. Pancreas

 

24.

What is the 1-year patient survival rate for renal transplant recipients?

A. > 90%

B. 60-70%

C. 25-50%

D. < 25%

E. Limited data available; currently an experimental procedure

 

20-5. Answers

1.

C. Lasix and Amaryl are structurally similar to sulfonamides and would be expected to elicit a similar allergic response. Dapsone is a sulfone and would not be expected to elicit an allergic response.

 

2.

B. Both azathioprine and CellCept are classified as antiproliferative agents. Both agents inhibit purine biosynthesis and would not act synergistically.

 

3.

A. Diflucan is an inhibitor of cytochrome P450 3A isoenzymes, which is the enzyme system that is responsible for metabolism of tacrolimus.

 

4.

D. Hyperkalemia (incidence 20-40%) is a well-documented adverse drug reaction with Prograf.

 

5.

D. Both cyclosporine and tacrolimus are calcineurin inhibitors.

 

6.

D. All of the listed agents have myelosuppressive properties when administered individually. When they are administered concurrently, the myelosuppression is synergistic.

 

7.

B. Cyclosporine is highly lipophilic and requires bile for emulsification and absorption.

 

8.

C. Hirsutism, nephrotoxicity, gingival hyperplasia, and hyperlipidemia are known adverse effects of cyclosporine. Oral ulceration is not an adverse effect of cyclosporine.

 

9.

C. The use of Rapamune (sirolimus) in de novo lung and liver transplant recipients is contraindicated because of an increased incidence of fatal adverse drug reactions. Additionally, use of Rapamune in patients with uncontrolled hyperlipidemia is strongly discouraged because of its profound effects on lipid biosynthesis and catabolism.

 

10.

B. Azathioprine is the generic name for Imuran.

 

11.

D. Prednisone and tacrolimus may cause diabetes mellitus. Azathioprine does not produce a diabetogenic effect.

 

12.

B. Prograf requires therapeutic drug monitoring via trough concentrations to obtain desired therapeutic effects.

 

13.

C. Daclizumab selects for destruction of activated lymphocytes by binding to the CD25 subunit of the high-affinity IL-2 receptor.

 

14.

C. Of the listed parameters, all are considered to increase the risk of acute rejection except a living donor as the donor source.

 

15.

A. Xanthine oxidase is responsible for the elimination of the active metabolites of azathioprine. Concomitant use of allopurinol with azathioprine results in significantly increased azathioprine-induced toxicity. Reduce the dose of azathioprine by 65-75%.

 

16.

D. Both biliary obstruction and severe malnutrition would change the pharmacokinetic profile of cyclosporine. Cyclosporine requires bile for emulsification and absorption. If bile flow is obstructed, then the bioavailability is significantly decreased. Additionally, cyclosporine is a highly lipoprotein-bound drug. In severe malnutrition, total protein stores are depleted, thereby increasing the total free drug.

 

17.

D. Both erythromycin and diltiazem are inhibitors of P450 3A isoenzymes, which is the enzyme system that is responsible for sirolimus metabolism.

 

18.

B. Simultaneous administration of Rapamune (sirolimus) and cyclosporine increases Cmax and area under the curve of sirolimus by 120-500% and 140-230%, respectively. Administration 4 hours apart increases Cmax and area under the curve of sirolimus by 30-40% and 35-80%, respectively.

 

19.

B. Innate immunity is the fundamental type of immunity in which antigens are recognized in a nonspecific manner. This type of immunity is not augmented on repeat exposure.

 

20.

C. Class I and II HLA are the actual antigens important for self- and nonself-recognition. The group of genes that encode for these antigens is the major histocompatibility complex.

 

21.

A. Activation is dependent on antigen-HLA binding to the T-cell receptor complex and the subsequent binding of a second signal or "co-stimulatory pathway."

 

22.

C. Active CD4+ T-cells produce and release various lymphokines, particularly IL-2, which is important for activation and proliferation of numerous lymphocyte lineages.

 

23.

C. The kidney was the first organ to be successfully transplanted, in 1954.

 

24.

A. According to Table 20-1, the 1-year patient survival rates for both cadaveric and living donor renal transplant recipients are 94.8% and 98.0%, respectively.

 

20-6. References

Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: Results of a 1-year study. Am J Transplant. 2003;4:237-43.

Christians U, Jacobsen W, Benet LZ, Lampen A. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clin Pharmacokinet. 2002;41:813-51.

Cotts WG, Johnson MR. The challenge of rejection and cardiac allograft vasculopathy. Heart Fail Rev. 2001;6:227-40.

Delves PJ, Roitt IM. The immune system: First of two parts. N Engl J Med. 2000;343:37-49.

Delves PJ, Roitt IM. The immune system: Second of two parts. N Engl J Med. 2000;343:108-17.

Dunn CJ, Wagstaff AJ, Perry CM, et al. Cyclosporin: An updated review of the pharmacokinetic properties, clinical efficacy, and tolerability of a microemulsion-based formulation (Neoral) in organ transplantation. Drugs. 2001;61:1957-2016.

Galley BJ, Perez RV, Ramsamooj R. Acute renal transplant injury and interaction between antithymocyte globulin and pooled human immunoglobulin. Clin Transplant. 2004;18:327-31.

Kelly P, Kahan BD. Review: Metabolism of immunosuppressant drugs. Curr Drug Metab. 2002;3: 275-87.

Klupp J, Holt DW, van Gelder T. How pharmacokinetic and pharmacodynamic drug monitoring can improve outcome in solid organ transplant recipients. Transpl Immunol. 2002;9:211-14.

Neuberger J. Incidence, timing, and risk factors for acute and chronic rejection. Liver Transpl Surg. 1999;5(suppl 1):S30-36.

Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant. 2003; 4:231-6.