Idelalisib

Uses

Idelalisib is an antineoplastic kinase inhibitor used to treat chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL).

Idelalisib is indicated in the treatment of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). For the treatment of relapsed CLL, it is currently indicated as a second-line agent in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities, while in the treatment of FL and SLL it is intended to be used in patients who have received at least two prior systemic therapies.

Idelalisib is also used to associated treatment for these conditions: Relapsed Chronic Lymphocytic Leukemia, Relapsed Small Lymphocytic Lymphoma, Relapsed follicular B-cell non-Hodgkin lymphoma

How Idelalisib works

Idelalisib specifically inhibits P110δ, the delta isoform of the enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase, also known as PI-3K. The PI-3Ks are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In contrast to the other class IA PI3Ks p110α and p110β, p110δ is principally expressed in leukocytes (white blood cells) and is important for the function of T cells, B cell, mast cells and neutrophils. By inhibiting this enzyme, idelalisib induces apoptosis of malignant cells and inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and C-X-C chemokine receptors type 5 and type 4 signalling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib has been shown to result in inhibition of chemotaxis and adhesion, and reduced cell viability.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A metabolism of idelalisib, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of idelalisib and may reduce its serum concentration.
• Take with or without food. Taking idelalisib with a high-fat meal may increase the AUC by 1.4 fold.

Idelalisib Alcohol interaction

[Moderate] GENERALLY AVOID:

Coadministration of idelalisib with other agents known to induce hepatotoxicity may potentiate the risk of liver injury.

The use of idelalisib has been associated with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 5 times the upper limit of normal.

Serious and fatal hepatotoxicity occurred in 14% of patients treated with idelalisib in premarketing trials.

Liver enzyme elevations were generally observed within the first 12 weeks of treatment and were reversible with dose interruption.

Following treatment resumption at a lower dose, 26% of patients had recurrence of ALT and AST elevations.

The use of idelalisib with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; amiodarone; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; methotrexate; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; tetracyclines; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice).

Patients treated with idelalisib should have serum ALT, AST, and bilirubin measured prior to initiation of treatment and regularly during treatment in accordance with the product labeling, and the dosing adjusted or interrupted as necessary.

Permanent discontinuation of idelalisib is recommended in those who experience recurrent hepatotoxicity following dosage reduction.

Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice.

Idelalisib Drug Interaction

Major: suvorexant, fluticasone / vilanterol, acetaminophen / oxycodoneModerate: bifidobacterium infantis, ciclesonide, lubiprostone, amoxicillin / clavulanate, azithromycin, vandetanib, celecoxib, loratadine, sulfamethoxazole / trimethoprim, bupropion / naltrexoneUnknown: crizanlizumab, darbepoetin alfa, aspirin, cyanocobalamin, fidaxomicin, hydroxyurea, cholecalciferol

Idelalisib Disease Interaction

Major: colitis, dermatologic toxicities, hepatic impairmentModerate: infections, intestinal perforation, neutropenia, lung toxicity

Volume of Distribution

23 L

Elimination Route

Following oral administration, the median Tmax was observed at 1.5 hours.

Half Life

The terminal elimination half-life is 8.2 hours.

Clearance

14.9 L/hr

Elimination Route

Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117, idelalisib's major metabolite, accounted for 49% of the radioactivity in the urine and 44% in the feces.

Innovators Monograph

You find simplified version here Idelalisib