Calcineurin Inhibitors
• What are Calcineurin Inhibitors?
• What are the agents used as Calcineurin Inhibitors?
• What is the MOA of Calcineurin Inhibitors?
• What are the different forms of Cyclosporine?
• What is Modified Cyclosporine?
• What is Non-Modified cyclosporine?
• Is Modified and Non-Modified Cyclosporine interchangeable?
• What are the formulations of cyclosporine?
• What is the dose of cyclosporine?
• What is the dosing of Tacrolimus?
• What is the conversion of IR à BID for Tacrolimus?
• How often do we dose XL/XR for Tacrolimus?
• What is the IV to PO conversion for Tacrolimus?
• What is the benefit of taking the IR capsule for Tacrolimus?
• What is the IR form of Tacrolimus?
• What are the ER forms Tacrolimus?
• What is the difference between Astagraf XL to Envasus XR for Tacrolimus?•
• What are the common side effects of Tacrolimus and Cyclosporine?
• What are the unique side effects of Tacrolimus?
• What are the unique side effects of Cyclosporine?
• What are the target range of Tacrolimus in the blood?
• How do we monitor Tacrolimus?
• What is the target range of Cyclosporine in the blood?
• How do we monitor Cyclosporine?
Calcineurin Inhibitors
• What do we measure for CNI?
• What do we not do prior to next blood draw for CNI?
• What is the issue of inaccurate blood levels?
Anti-Proliferatives/ Anti-Metabolites
• What are the antiproliferatives/antimetabolites?
• What are the different formulations of Mycophenolate?
• What is the MOA of Mycophenolate?
• What is the dose of Mycophenolate?
• What is the Dose conversion of CellCept to Mofetil?
• What is the IV:PO conversion of Mycophenolate?
• What are the side effects of Mycophenolate?
• What are the GI side effects associated with Mycophenolate?
• What is unique about Mycophenolate?
• What are the reasons Mycophenolate is under REMS?
• What do we need to provide counseling about for
Mycophenolate?
• How do we plan for pregnancy with Mycophenolate?
• What is Azathioprine known as?
• What is the MOA of Azathioprine?
• What is the dose of Azathioprine?
• How does Azathioprine work?
• What does Azathioprine inhibit?
• What is Azathioprine replaced by?
Mammalian Target of Rapamycin
• What is m-TOR?
• What are the drugs that target m-TOR?
• What happens when we target mTOR?
• What is the monitoring required of mTOR agents?
• What conditions do we best recommend mTOR inhibitors for?
• What are the side effects of mTOR inhibitors?
• When does Nephrotoxicity/Neurotoxicity occur
with mTOR I?
Co-stimulation Blockers
• What is the co-stimulation inhibitor used as a
maintenance therapeutic agent?
• What is the MOA of Belatacept?
• What is the benefit of using Belatacept?
• What is Belatacept approved only for?
• What is the issue with Belatacept?
• Who is Belatacept only used for?
• What is the issue of Belatacept for use in
Liver-transplant patients?
• What are the adverse effects of Belatacept?
Corticosteroids
• What are the different corticosteroids used?
• What do Corticosteroids affect?
• Who receives corticosteroids?
• How do we taper corticosteroids?
• What are the causes of Lymphopenia associated with
corticosteroids?
• What are the causes of reduced APCs and Reduced T cells with
APCs?
• What are the adverse effects of corticosteroids?
Treatment
• What is the typical regimen for transplant therapy?
• What are the common ways for maintenance therapy?
Drug Interactions
• What are the common interactions of Transplant inductive
and Maintenance therapies?
• What are common 3A4 Substrates?
• What are common 3A4 inhibitor interactions?
• What are the common 3A4 inducer interactions?
• What do we avoid with transplant patients for OTCs?
• What OTCs are safe after transplant?
• They are the backbone of current immunosuppression
• Tacrolimus and Cyclosporine (Similar ADEs and MOA)
• CNIs form a complex that binds calcineurin which prevents
the expression of T-cell
activators (IL-2, TNF-A, IL-4, IFN-G)
• There is Modified and Non-Modified Cyclosporine
• Neoral and GenGraf
• Sandimmune
• No, they are NOT interchangeable
• PO and IV formulation
• 100-2o0 mg BID
• 4-8mg/d
• IR=BID
• Daily Dose
• 1:4
• IR can be taken sublingually
• Prograf
• Astragraf XL; Envarsus XR
Astragraf (1) : Envarsus XR (0.8)
• Nephrotoxicity, Neurotoxicity; Hypertension; Hypomagnesemia; Hyperkalemia
• Alopecia; Pancreatic Islet Toxicity
• Hirsutism; Gingival Hyperplasia; Hyperlipidemia
• 5-15ng/mL
• Dose/Trough: Institution, Organ-specific: requires drug level monitoring for life
• 50-300ng/mL
• Target trough level range is modified by: induction agents;
additional
immunosuppressive agents; kidney dysfunction rejection and
infection history
• Trough Levels- 30 min prior to next dose
• Do NOT take CNI inhibitor prior to blood draw
• Inaccurate trough levels can lead to inappropriate dosage adjustments
• Mycophenolate; Azathioprine
• Mycophenolate Mofetil (Cellcept); Mycophenolate Sodium (Myfortic)
• Inhibits inosine monophosphate dehydrogenase (MPDH)
and prevents
denovo synthesis in lymphocytes (active agent is mycophenolic
acid-MPA)
• 1000mg PO BIDà dose adjustments may be required
• Cellcept:1000mg= Myfortic:720mg
• 1:1
• GI Side Effects most common; Leukopenia, thrombocytopenia, Anemia; Teratogenic
• Nausea, Vomiting, Diarrhea à may require dose reduction or discontinuation
• It has a Risk Evaluation and Mitigation Strategy Program
• Causes to lose the first-trimester pregnancy; congenital malformations
• Contraceptive Counseling
• Must stop medication for 6 weeks; switch to an alternative agent
• Imuran; Azasan, AZA
• Prodrug converted to 6-mercaptopurine
• 50-150mg daily
• Incorporates into cellular DNA, which interferes with the
synthesis of
RNA and Metabolism
• Inhibits gene replication -- > no T cell activation;
also inhibits the proliferation of promyelocytes in the marrow
• MMF and mTORi
• Mammalian Target of Rapamycin
• Sirolimus and Everolimus
• These drugs bind to mTOR which results in the arrest of the
cell cycle at G1;
inhibits the proliferation of many cell lines (lymphoid, CNS,
Hepatic; Melanocytic
• Dose Trough Levels (Institution Specific; Requires monitoring for life)
• History of Cancer (HCC in Liver Transplant); Intolerance of
CNIs;
History of Viral Infections (BK Virus)
• Hepatic Artery Thrombosis; Impaired Wound Healing;
Neurotoxicity; Nephrotoxicity;
Interstital Pneumonitis/Alveolar Hemorrhage; Thrombocytopenia,
Leukopenia; Hyperlipidemia; Peripheral Edema; Mouth Ulcers
• When used with CNI
• Belatacept (Nulojix)
• Binds surface receptors CD80/CD86 of Antigen Presenting
Cells; Inhibits the interaction
between APCs and T cells which are needed for T-Cell Activation
• May replace CNI in maintenance immunosuppressive Agents
(avoids nephrotoxicity;
once monthly infusion)
• Kidney Transplant Patients
• It has a blacked box warning- causing post-transplant lymphoproliferative disorder
• Epstein-Barr Virus Positive Patients
• Causes the increased risk of graft loss and death
• Anemia; Headache, NVD
• Prednisone, Prednisolone, Methylprednisolone
• Effects most cells in the body; non-specific MOA
• Everyone who has a transplant
• Taper rapidly over the first 5 days
• Nonspecific immunosuppressive effets
• Corticosteroids binding directly to GRE, inhibiting NFK-B
causing a reduction
in the release of cytokines (IL-1, IL-2, IL-3, IL-6, TNF, IFN-G)
• Cataracts; Impaired Wound Healing; Glucose Intolerance;
Psychopathologic Effects;
Dyslipidemia; Cosmetic Changes (Acne, Hair Growth); Growth
Impairment; Osteoporosis; GI Ulceration/upset
• Induction: Corticosteroid +/- Depleting v. Non-Depleting Agent
• Maintenance: 2-3 medications : CNI, Corticosteroid, Antiproliferative
• CYP3A4 Substrates, Inhibitors, Inducers
• Cyclosporine. Everolimus, Sirolimus Tacrolimus
• Calcium Channel Blockers; Antifungal Agents; Antibiotics;
Food; Protease Inhibitors;
Amiodarone/Cemitidine/Colchistat
• Anticonvulsants; Herbal Preparations; Antibiotics
• Avoid NSAIDs; Naproxen, Ibuprofen
• Acetaminophen, Diphenhydramine, Guaifenesin, Colace, Senna