DRUG STUDY AND INFORMATION FORM Generic Name: Thalidomide Trade Name: Thalomid Drug Class: Inhibitors of Angiogenesis

Structure/Chemistry: Has a chiral carbon where the two ring structures attach at C-N bond. Appears as two non-polar S(-) (associated with sedative properties) and R(+) isomers (equilibrium favors R product, associated with teratogenic and biological properties).

Pharmacodynamics

Mechanism of Action: The precise mechanisms are unclear due to thalidomides enantiomeric interconversion and spontaneous cleavage to multiple short-lived and poorly characterized metabolites. Four possibilities are proposed: 1. Direct anti-proliferative/pro-apoptotic antitumor effects by inhibiting NF-B and a Bcl-2 family member. 2. Indirect inhibition of tumor cell growth and survival by abrogation of cell interactions with adhesion molecules. 3. Inhibition of IL-6 and TNF- production, release, and signaling, leading to anti-angiogenic effects. 4. Immunomodulation through enhancement of NK and T cell-mediated cytotoxicity. Pharmacologic Effects: An anti-angiogenic and immunomodulatory compound that promotes apoptosis and inhibits angiogenesis. It also inhibits MM-cell adhesion to bone marrow stroma and enhances T-cell production of cytokines (such as IL-2 and IFN-) that increase the number and cytotoxic functionality of NK cells.

Drug Resistance or Tolerance:

Pharmacokinetics

Absorption: Absorption is slow and highly variable through GI tract. Doses begin as 2001200 mg/day. Doses are usually escalated 200 mg/day every 2 weeks until dose-limiting side effects supervene. Distribution: Distributes to most tissues and organs without significant binding to plasma proteins. Elimination: t1/2 of 6 hours. Eliminated mainly by spontaneous hydrolysis in body fluids. Senantiomer cleared more rapidly than R-enantiomer. Excreted in the urine.

Metabolism:

Adverse Side Effects/Toxicity: Highly teratogenic and causes dysmelia (stunted limb growth). High doses correspond with sedation, fatigue, constipation, and peripheral sensory neuropathy (most serious; worsens with higher doses). May increase the likelihood of thromboembolic events. Drug Interactions: Observed clinical synergy with glucocorticoids and bortezomib against MM. Enhances sedative effects of barbituates and alcohol and the catatonic effects of chlorpromazine and reserpine. CNS stimulates (methamphetamine and methylphenidate) counteract the depressant effects of thalidomide.

Therapeutic uses: Potent activity against new and refractory/relapsed multiple myeloma

Miscellaneous: Devastatingly originally used for pregnancy-associated morning sickness. Caution should be used in patients with pre-existing neuropathy.