Venetoclax

Uses

Venetoclax is a BCL-2 inhibitor used to treat chronic lymphocytic leukemia, small lymphocytic lymphoma, or acute myeloid leukemia.

A BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy .

Venetoclax is also used to associated treatment for these conditions: Chronic Lymphocytic Leukaemia (CLL), Small Lymphocytic Lymphoma

How Venetoclax works

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are necessary regulators of the apoptotic (anti-cell programmed death) process. This family comprises proapoptotic and prosurvival proteins for various cells. Cancer cells evade apoptosis by inhibiting programmed cell death (apoptosis). The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has demonstrated clinical efficacy in some BCL-2-dependent hematological cancers . Selective inhibition of BCL-2 by venetoclax, sparing BCL-xL enables therapeutic induction of apoptosis without the negative effect of thrombocytopenia , . Venetoclax helps restore the process of apoptosis by binding directly to the BCL-2 protein, displacing pro-apoptotic proteins, leading to mitochondrial outer membrane permeabilization and the activation of caspase enzymes. In nonclinical studies, venetoclax has shown cytotoxic activity in tumor cells that overexpress BCL-2 .

Toxicity

Acute toxicity: oral toxicity (LD50) >2001 mg/kg (mouse) .

Venetoclax may cause embryo-fetal harm when administered to a pregnant woman. Patients should avoid pregnancy during treatment. A risk to human male fertility exists based on the results of testicular toxicity (germ cell loss) seen in dogs at exposures as low as 0.5 times the human AUC exposure at the recommended dose .

Carcinogenicity studies have not yet been performed with venetoclax .

Venetoclax was not shown to be mutagenic in an in vitro bacterial mutagenicity (Ames) assay, did not induce aberrations in an in vitro chromosome aberration assay with human peripheral blood lymphocytes. It was not clastogenic in an in vivo mouse bone marrow micronucleus assay at doses up to 835 mg/kg. The M27 metabolite was negative for genotoxic activity during both in vitro Ames and chromosome aberration assays .

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of venetoclax.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of venetoclax.
• Take at the same time every day.
• Take with a full glass of water.
• Take with food.

[Major] ADJUST DOSING INTERVAL: Food enhances the oral bioavailability of venetoclax.

Relative to fasting conditions, venetoclax systemic exposure (AUC) increased by approximately 3.4-fold when administered with a low-fat meal and by 5.1- to 5.3-fold when administered with a high-fat meal.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of venetoclax.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased venetoclax exposure may potentiate the risk of tumor lysis syndrome, particularly at initiation of therapy and during the dosage ramp-up phase, as well as other adverse effects such as diarrhea, nausea, vomiting, neutropenia, anemia, and thrombocytopenia.

MANAGEMENT: Venetoclax should be administered with a meal and water at approximately the same time each day.

Patients should avoid consumption of grapefruit products, Seville oranges, and starfruit during treatment with venetoclax.

Venetoclax Drug Interaction

Moderate: apixabanUnknown: aspirin, diphenhydramine, loratadine, prochlorperazine, obinutuzumab, arginine, levocarnitine, cysteine, escitalopram, lithium, acetaminophen, valproic acid, valacyclovir, thiamine, cyanocobalamin, pyridoxine, cholecalciferol, phytonadione, menaquinone

Venetoclax Disease Interaction

Moderate: hepatic impairment, neutropenia, TLS/renal, vaccination

Volume of Distribution

The population estimate for apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L .

Elimination Route

Following several oral administrations after a meal, the maximum plasma concentration of venetoclax was reached 5-8 hours after the dose . Venetoclax steady state AUC (area under the curve) increased proportionally over the dose range of 150-800 mg. After a low-fat meal, venetoclax mean (± standard deviation) steady-state Cmax was 2.1 ± 1.1 μg/mL and AUC0-24 was 32.8 ± 16.9 μg•h/mL at the 400 mg once daily dose .

When compared with the fasted state, venetoclax exposure increased by 3.4 times when ingested with a low-fat meal and 5.2 times with a high-fat meal. When comparing low versus high fat, the Cmax and AUC were both increased by 50% when ingested with a high-fat meal. The FDA label indicataes that venetoclax should be taken with food , .

Half Life

The half-life of venetoclax is reported to be 19-26 hours, after administration of a single 50-mg dose , .

Clearance

Mainly hepatic .

Elimination Route

After single oral administration of 200 mg radiolabeled [14C]-venetoclax dose to healthy subjects, >99.9% of the dose was found in feces and Label.

Innovators Monograph

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