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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 907

Absorption, Fate, and Excretion: Lenalidomide is rapidly mean half-life of temsirolimus is 17.3 hours, and the mean half-life
absorbed after oral administration. Lenalidomide has a half-life of 3 of sirolimus, the active metabolite, is 54.6 hours. Neither the parent
hours with 67% of the drug excreted unchanged in the urine. Adjust- drug nor its metabolite is dialyzable. Dosage reduction or discontinu-
ment to the initial dosage is recommended in patients with moderate ance may be warranted in patients with hepatic impairment to reduce
or severe renal impairment. Compared with patients with normal the potential for toxicity.
renal function, those with moderate and severe renal impairment have
a 66%–75% decrease in drug clearance, and patients on hemodialysis Preparation and Administration: Temsirolimus is supplied as a
have an 80% decrease in clearance. Although the drug is 30% protein kit consisting of two vials: temsirolimus injection (25 mg/mL) and a
bound, lenalidomide is partially removed by hemodialysis and should diluent of 1.8 mL. Temsirolimus is mixed with 1.8 mL of the diluent.
be given after dialysis. Food does not alter the extent of absorption The resultant solution contains 10 mg/mL. The concentrate–diluent
nor the AUC of lenalidomide. mixture is stable below 25°C for up to 24 hours. To administer,
withdraw the required amount of concentrate–diluent mixture and
Preparation and Administration: Lenalidomide is available in further dilute into an infusion bag containing 250 mL of 0.9%
2.5-, 5-, 10-, 15-, and 25-mg capsules for PO administration. Each sodium chloride injection, USP. Patients should receive prophylactic
capsule contains lenalidomide as the active ingredient along with IV diphenhydramine 25 mg before the start of each dose.
lactose anhydrous, microcrystalline cellulose, croscarmellose sodium,
and magnesium stearate. Toxic Effects: Temsirolimus causes a decreased lymphocyte count,
leucopenia, decreased hemoglobin, and thrombocytopenia. Hyper-
Toxic Effects: Lenalidomide frequently may cause deep venous glycemia, edema, and rash (which may progress to Stevens-Johnson
thrombosis and pulmonary embolism. Severe myelosuppression syndrome) have also been seen.
across all cell lines is common. Pruritus and rash as well as constipa-
tion and hypokalemia are seen. Lenalidomide is an analogue of tha- Drug Interactions: The concomitant use of strong CYP3A4
lidomide and may cause birth defects in humans. It must not be given inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazana-
during pregnancy. vir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithro-
mycin, and voriconazole) may increase plasma concentrations of
Drug Interactions: Lenalidomide increases digoxin plasma con- sirolimus (a major metabolite of temsirolimus). The use of concomi-
centrations. Dexamethasone increases the thrombogenic effect of tant strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, car-
lenalidomide. bamazepine, rifampin, rifabutin, rifampicin, phenobarbital) may
decrease plasma concentrations of sirolimus (a major metabolite of
Therapeutic Indications in Hematology: Lenalidomide has temsirolimus).
activity in MM when used in combination with dexamethasone. It
also is has activity in chronic lymphoid leukemia as well as MDS with Therapeutic Indications in Hematology: Temsirolimus has
deletion 5q abnormlalities. been shown to have activity in MCL.
Pomalidomide Everolimus
Chemistry and Mechanism of Action: Pomalidomide is struc- Chemistry and Mechanism of Action: Everolimus is an
turally and functionally related to thalidomide. Its mechanism is not analogue of rapamycin (sirolimus) with immunosuppressive and
fully understood but it has effects on angiogenesis, alters inflamma- antiproliferative activity. Everolimus is an inhibitor of rapamycin
tory and regulatory cytokines, and may affect T cells. (mTOR), a serine–threonine kinase, downstream of the PI3K/AKT
pathway. After binding and forming a complex with the cytoplasmic
Absorption, Fate, and Excretion: Pomalidomide is adminis- FK506-binding protein 12 (FKBP-12), the complex binds to and
tered orally. Pharmacokinetic data are still being elucidated. inhibits mTOR and phosphorylates P70 S6 ribosomal protein
kinase (a substrate of mTOR). Everolimus reduces the activity of S6
Preparation and Administration: Pomalidomide is an investi- ribosomal protein kinase (S6K1) and eukaryotic elongation factor
gational agent administered orally. 4E–binding protein. In addition, everolimus inhibits the expres-
sion of hypoxia-inducible factor 1 and reduces the expression of
Toxic Effects: Pomalidomide has extensive bone marrow toxicity VEGF.
affecting all three cell lines, peripheral neuropathy, orthostasis, rashes,
pulmonary toxicity, and clotting abnormalities. Absorption, Fate, and Excretion: Peak everolimus concentra-
tions are reached 1–2 hours after oral administration with protein
Drug Interactions: Data not available. binding of 74%. Everolimus is extensively metabolized by the liver,
with everolimus being a substrate of CYP3A4 and PGP. Metabolism
Therapeutic Indications in Hematology: Pomalidomide has involves demethylation, hydroxylation, and ring degradation. There
been studied in MM. are six main metabolites of everolimus, which have approximately
100-times less activity than the parent everolimus compound, includ-
Temsirolimus ing three monohydroxylated metabolites, two hydrolytic ring-opened
metabolites, and a phosphatidylcholine conjugate of everolimus. The
Chemistry and Mechanism of Action: Temsirolimus is an elimination half-life is 30 hours and is prolonged to a mean of 79
inhibitor of mammalian target of rapamycin (mTOR) and binds to hours in patients with moderate hepatic impairment.
an intracellular protein (FKBP-12). This protein–drug complex
inhibits the activity of mTOR and results in G1 growth arrest. When Preparation and Administration: Everolimus is available in
mTOR is inhibited, its ability to phosphorylate p70S6k and S6 2.5-, 5-, 7.5- and 10-mg nonscored tablets.
ribosomal protein, which are downstream of mTOR in the PI3K/
AKT pathway, was blocked. Toxic Effects: Everolimus causes bone marrow suppression across
all cell lines, hyperglycemia, rash, and mucositis along with pulmo-
Absorption, Fate, and Excretion: Temsirolimus is predomi- nary toxicity.
nately metabolized in human liver microsomes by cytochrome P450
3A4 (CYP3A4). Temsirolimus is extensively metabolized to sirolimus. Drug Interactions: Everolimus concentrations are increased when
Four other metabolites account for less than 10% in the plasma. The administered with CYP3A4 or PGP inhibitors such as ketoconazole,