Page 1023 - Hematology_ Basic Principles and Practice ( PDFDrive )

906 Part VII Hematologic Malignancies

A P P E N D I X 57.6

CLINICAL PHARMACOLOGY OF MISCELLANEOUS AGENTS

Idelalisib Thalidomide
Chemistry and Mechanism of Action: Idelalisib is an inhibitor Chemistry and Mechanism of Action: The mechanism of
of PI3Kδ kinase, which is expressed in normal and malignant B cells. action of thalidomide is not fully understood. Thalidomide has
Idelalisib induces apoptosis and inhibits proliferation in cell lines immunomodulatory, antiinflammatory, and antiangiogenic proper-
derived from malignant B cells and in primary tumor cells. Idelalisib ties. The immunologic effects vary substantially under differing
inhibits several cell signaling pathways, including B-cell receptor conditions but seem to suppress TNF-α production and downmodu-
(BCR) signaling and CXC-chemokine receptor (CXCR)4 and late cell surface adhesion molecules. Other antiinflammatory and
CXCR5 signaling, which are involved in trafficking and homing of immunomodulatory properties include suppression of macrophage
B cells to the lymph nodes and bone marrow. involvement in prostaglandin synthesis and modulation of IL-10 and
IL-12 production by peripheral blood mononuclear cells. Angiogen-
Absorption, Fate, and Excretion: Idelalisib is metabolized via esis inhibition is described, but the exact mechanism is not yet
aldehyde oxidase and CYP3A to an inactive metabolite. It is 84% definitively defined.
protein bound, with a half-life of 8.2 hours. AUC is increased up
to1.7-fold in subjects with ALT or AST, or bilirubin values greater Absorption, Fate, and Excretion: Thalidomide absorption is
than the upper limit of normal (ULN) compared with subjects with slow after oral administration, and the bioavailability of capsules has
normal AST or ALT or bilirubin values. CLcr has no effect on ide- not yet been determined, but based on radiolabeled thalidomide,
lalisib exposure. No dose adjustment is needed for patients with CLcr greater than 90% is recovered in urine, suggesting good oral absorp-
≥15 mL/min. tion. The mean elimination half-life of thalidomide ranges from 3 to
6.7 hours, but the exact metabolic fate of thalidomide is unknown.
Preparation and Administration: Idelalisib is available as a Protein binding is 55%–66%.
100-mg orange oval tablet as well as a 150-mg pink oval tablet.
Preparation and Administration: Thalidomide is available as
Toxic Effects: Fatal and/or serious hepatotoxicity occurred in 14% 50-, 100-, 150-, and 200-mg PO capsules. A 20-mg/mL PO suspen-
of patients treated with idelalisib. Severe diarrhea or colitis with sion may be prepared with capsules and a 1 : 1 mixture of Ora-Sweet
possible perforation occurred in 14% of patients. Fatal and serious and Ora-Plus by emptying the contents of twelve 100-mg capsules
pneumonitis as well as grade ≥3 cutaneous reactions were also seen. into a glass mortar. Add small portions of the vehicle and mix to a
31% of patients treated also had significant neutropenia. uniform paste; mix while adding the vehicle in incremental propor-
tions to almost 60 mL; transfer to an amber calibrated bottle and add
Potential Drug Interactions: All drugs undergoing metabolism quantity of vehicle sufficient to make 60 mL. Stable for 35 days
by the CYP3A pathway should be used with caution. refrigerated.

Therapeutic Indications in Hematology: Follicular lymphoma, Toxic Effects: Thalidomide frequently may cause deep venous
small lymphocytic lymphoma, and CLL. thrombosis and pulmonary embolism. Thalidomide causes birth
defects in humans. It must not be given during pregnancy. Leucope-
Oblimersen nia along with thrombocytopenia is observed. Pruritus and rash as
well as constipation are seen.
Chemistry and Mechanism of Action: Oblimersen is an
18-mer phosphorothioate antisense oligonucleotide that targets Drug Interactions: Thalidomide increases cyclosporine A metabo-
human Bcl-2 mRNA and prevents Bcl-2 expression. Oblimersen lism and clearance. An increase in the thrombogenic state in patients
downregulates Bcl-2 expression, with enhancement of tumor cell with MDS has been observed in patients receiving darbepoetin alfa
apoptosis. and thalidomide. The addition of docetaxel to thalidomide increases
the risk of venous thromboembolism.
Absorption, Fate, and Excretion: The half-life of oblimersen
averages 0.5–2 hours, and it is excreted primarily unchanged in the Therapeutic Indications in Hematology: Thalidomide has
urine. been used to treat MM and MDS.
Preparation and Administration: Oblimersen is given by con- Lenalidomide
tinuous IV infusion or subcutaneously.
Chemistry and Mechanism of Action: Lenalidomide, a thalido-
Toxic Effects: Oblimersen is associated with hyperglycemia, diar- mide analog, is an immunomodulatory agent with antineoplastic and
rhea, thrombocytopenia, and hepatic toxicity. antiangiogenic activity. Lenalidomide affects ligand-induced responses
(angiogenesis, inflammation, cell adhesion, immune response), inhibits
Potential Drug Interactions: Unknown. production of TNF, increases production of IL-2 and IFN-γ, and
increases cytolytic T-cell and NK cell responses. It inhibits trophic
Therapeutic Indications in Hematology: AML, NHL, and signals to angiogenic factors in cells, and inhibits growth of myeloma
MM. cells by inducing cell cycle arrest and apoptosis.