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Thalidomide

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Thalidomide, Thalidomid, Cereblon Modulator, Immunomodulatory Phthalimide, Lenalidomide, Revlimid, Pomalidomide, Pomalyst

  • History
  1. Thalidomide was originally introduced in the U.S. in the 1950s as a Sedative and Antiemetic in Hyperemesis Gravidarum
    1. Identified as a highly Teratogenic agent and pulled from the U.S. market
    2. More than 10,000 children were born with serious congenital malformations attributed to Thalidomide
  2. Later, in the 1990s, Thalidomide was reinvestigated as an immunomodulatory agent
    1. Thalidomide is a complex drug that spontaneously hydrolyzes to 20 metabolites in vivo
    2. Thalidomide was among the first TNFa agents
    3. Thalidomide has since been approved for Multiple Myeloma and many Autoimmune Conditions
    4. Related drugs, Lenalidomide and Pomalidomide have since been developed
  • Indications
  • Thalidomide
  1. Autoimmune Conditions
    1. Erythema Nodosum leprosum
    2. Crohn Disease
  2. Malignancy
    1. Multiple Myeloma
    2. Myelodysplastic Syndrome
    3. Primary Brain Tumors
    4. Kaposi Sarcoma
  3. Transplant
    1. Graft Versus Host Disease
    2. Hematopoietic Stem Cell Transplantation
  4. Infectious Disease
    1. Mycobacterial infection
    2. HIV Wasting Syndrome
  5. Miscellaneous Conditions
    1. Severe recurrent Aphthous Stomatitis
    2. Hereditary Hemorrhagic Telangiectasia.
  • Indications
  • Thalidomide Analogs
  1. Lenalidomide (Revlimid)
    1. Multiple Myeloma
    2. Myelodysplastic Syndromes (deletion 5q)
    3. Mantle cell Lymphoma
    4. Follicular Lymphoma
    5. Marginal zone Lymphoma
  2. Pomalidomide (Pomalyst)
    1. Multiple Myeloma
    2. AIDS-related Kaposi Sarcoma
  • Contraindications
  1. Pregnancy (black box warning, REMS)
  2. Risk of Venous Thromboembolism (relative contraindication)
  • Mechanism
  1. Glutamic Acid synthetic derivatives with immunomodulatory and antinflammatory effects
  2. Immunomodulatory effects are related to its binding and blocking the Protein Cereblon
  3. Inhibit Tumor Necrosis Factor alpha (TNFa)
    1. Inhibits activated peripheral Monocytes and their chemotaxis
    2. Inhibits Neutrophil chemotaxis
    3. Inhibits Interleukin and Interferon activity
  4. Inhibits pro-Angiogenesis factors
    1. Vascular Endothelial Growth Factor (VEGF)
    2. Basic Fibroblast Growth Factor (bFGF)
  5. Other effects
    1. Promotes T Cell and Natural Killer (NK) cell activity
    2. Promotes Antibody-dependent cellular cytotoxicity (ADCC)
  • Medications
  1. Thalidomide (Thalidomid)
  2. Thalidomide Analogs
    1. Lenalidomide (Revlimid)
    2. Pomalidomide (Pomalyst)
      1. Orally Bioavailable derivative of Thalidomide
  • Dosing
  1. See other references for disease specific dosing protocols
  • Pharmacokinetics
  • Thalidomide
  1. Variable oral Bioavailability
  2. Peak activity 2 to 5 hours after oral dose
  3. Half-Life: 5-7 hours
  4. Renal excretion: 90%
  • Adverse Effects
  • Thalidomide and Analogs
  1. Highly Teratogenic (see below)
  2. Cardiovascular
    1. Venous Thromboembolism
    2. Ischemic Heart Disease (including Myocardial Infarction)
    3. Cerebrovascular Accident
    4. Orthostatic Hypotension
    5. Bradycardia
  3. Neuropsychiatric effects
    1. Peripheral Neuropathy
    2. Sedation
    3. Headache
    4. Mood change
  4. Endocrine effects
    1. Hypothyroidism
    2. ACTH Stimulation
    3. Hypoglycemia
  5. Hematologic
    1. Neutropenia
    2. Thrombocytopenia
    3. Tumor Lysis Syndrome
    4. Secondary primary malignancy
  6. Other effects
    1. Constipation
    2. Rash (including Stevens-Johnson Syndrome)
    3. Hepatotoxicity (Pomalidomide, Lenalidomide)
  • Safety
  1. Avoid in Lactation
  2. Avoid in pregnancy (all trimesters, Pregnancy category X)
    1. Use two forms of reliable Contraception
    2. Male patients should use a Condom or abstain from intercourse
  3. Monitoring
    1. Complete Blood Count
    2. Periodic complete Neurologic Exams (every 6 months)
    3. Liver Function Test (Pomalidomide, Lenalidomide)
  • Drug Interactions
  1. Strong CYP1A2 Inhibitors
    1. Avoid with Pomalidomide
  2. Digoxin
    1. Lenalidomide may increase levels
  • Resources
  1. Thalidomide (StatPearls)
    1. https://www.ncbi.nlm.nih.gov/books/NBK557706
  2. Thalidomide (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2eda833b-1357-4ed4-a093-194524fcb061
  3. Lenalidomide (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296be
  4. Pomalidomide (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2b25ef01-5c9e-11e1-b86c-0800200c9a66