Thalidomide And Lenalidomide

Thalidomide has been reintroduced to clinical practice as an oral agent for the management of erythema nodosum leprosum (ENL) and in other disease settings, most notably MM. Lenalidomide is a thalidomide derivative with improved potency and safety profile compared to thalidomide. Thalidomide is a nonpolar racemic mixture of cell permeable and rapidly interconverting S(-) and R(+) isomers. The precise mechanisms responsible for thalidomide's clinical activity remain to be elucidated. Multiple distinct, but potentially complementary, mechanisms have been proposed to explain the antitumor activity of thalidomide and its derivatives, including stimulation of T cells and NK cells, inhibition of angiogenesis and tumor cell proliferation, and modulation of hematopoietic stem cell differentiation (Figure 51-6).

Thalidomide absorption from the GI tract is slow and highly variable (4 hours to reach peak concentration, with a range of 1—7 hours). It is widely distributed throughout most tissues and organs, with a large apparent volume of distribution. Thalidomide metabolism via hepatic CYPs is limited, and no induction of its own metabolism is noted with prolonged use. Elimination of thalidomide is mainly by spontaneous nonenzymatic hydrolysis, which occurs in all body fluids, with an apparent mean clearance of 10 L/h for the (R)-enantiomer and 21 L/h for the (S)-enantiomer in adults. Thalidomide and over 50 metabolites are rapidly excreted in the urine, while the nonab-sorbed portion of the drug is excreted unchanged in feces. Both single and multiple dosing of thalidomide in elderly prostate cancer patients shows significantly longer t1/2 at higher doses (1200 mg daily) versus lower doses (200 mg daily). Conversely, no effect of increased age on elimination t/2 was identified in the age range of 55-80 years. The impact of renal or hepatic dysfunction on thalidomide clearance remains to be defined.

Lenalidomide is rapidly absorbed following oral administration, with peak plasma levels occurring 0.6-1.5 hourspostdose. The AUC values increase proportionately with increasing dose, both over a single-dose range of 5-400 mg and after multiple dosing with 100 mg daily. The t122 increases with dose, from ~3 hours at the 5-mg dose, to ~9 hours at the 400-mg dose (the higher dose is believed to provide a better estimate of the t1/2 due to the prolonged elimination phase). Approximately 70% of the orally administered dose of lenalidomide is excreted by the kidney.

Thalidomide (thalomid) is used to treat patients with relapsed and refractory MM, as well as early stage disease. The National Comprehensive Cancer Network (NCCN; www.nccn.org) Clinical Practice Guidelines for Multiple Myeloma includes thalidomide as an option for salvage therapy in patients with relapsed or refractory MM, or as initial therapy in combination with dexamethasone for patients with advanced myeloma. Thalidomide is also in clinical trials for use in treating a variety of solid tumors and myelodysplasias.

Lenalidomide (revlimid) is approved for treatment of transfusion-dependent anemia due to low- or intermediate-risk myelodysplastic syndromes associated with the 5q cytogenetic deletion, with or without additional cytogenetic abnormalities. It is being examined for use in combination with dexam-ethasone in newly diagnosed patients with MM, and in combination with agents such as bortezomib in relapsed and refractory MM. It is also being evaluated for use in treating many of the same neoplasias for which thalidomide might be useful, including myelodysplastic syndromes and certain solid tumors.

Thalidomide generally is well tolerated at doses <200 mg daily, the typical doses used to treat MM and ENL. The most common adverse effects reported in cancer patients are sedation and constipation, while the most serious one is treatment-emergent peripheral neuropathy, which occurs in 10-30% of patients with MM or other malignancies in a dose- and time-dependent manner. Thalidomide-related neuropathy is an asymmetric, painful, peripheral paresthesia with sensory loss, commonly presenting with numbness of toes and feet, muscle cramps, weakness, signs of pyramidal tract involvement, and carpal tunnel syndrome. The incidence of peripheral neuropathy increases with higher cumulative doses of thalidomide, especially in elderly patients. Although clinical improvement typically occurs upon drug discontinuation, long-standing residual sensory loss can occur. Particular caution should be applied in cancer patients with preexisting neuropathy (e.g., related to diabetes) or prior exposure to drugs that can cause peripheral neuropathy (e.g., vinca alkaloids or bortezomib). An increasing incidence of thromboembolic events in

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