Venetoclax

MECHANISM OF ACTION:

Venetoclax involves targeting a specific protein called BCL-2. BCL-2 acts like a cell’s on/off switch for death, preventing a natural process called apoptosis from eliminating unwanted cells. Cancerous blood cells, particularly in CLL, SLL, and AML, often overproduce BCL-2, making them resistant to traditional chemotherapy. Venetoclax binds directly to BCL-2, essentially flipping the cell’s death switch back on causing the cell to die. 

PHARMACOKINETICS:

Absorption: After oral dosing, the maximum plasma concentration ranged from 5 to 8h, and the mean half-life ranged from 4 to 18h. Food increases venetoclax bioavailability by 3-5-fold and venetoclax should be administered with food to ensure adequate and consistent bioavailability.

Distribution: The apparent volume of distribution of venetoclax ranges between 256 – 231L.

Metabolism: Venetoclax is predominantly metabolized by CYP3A4/5 to form a major metabolite M27, which is considered pharmacologically inactive. The estimated half-life of venetoclax is 26 hours.

Excretion: Approximately 100% of the administered radioactive dose was recovered in the feces, with 21% as unchanged venetoclax.

PHARMACODYNAMICS: 

An average steady-state venetoclax concentration of 0.00863µg/mL would decrease lymphocyte counts in patients with R/R CLL and NHL by 50%. The average steady-state venetoclax concentration that would decrease lymph node tumor size by 50% is 0.146µg/mL approximately 17-fold higher than that for circulating lymphocyte counts.

DOSAGE AND ADMINISTRATION:

In general, the recommended amount dose of venetoclax increased weekly. In the first week of the treatment, the dose starts from 20mg once a day orally and exceeds 400mg or more per day in the fifth week.

In combination with obinutuzumab, it starts obinutuzumab at 100mg orally on cycle 1 Day 1, followed by 900mg on cycle 1 day 2 then 1000mg orally on days  8 and 15 of cycle 1 and on day 1 of each subsequent 28-day cycle, for a total 6 cycles. 

On cycle 1 day 22, start venetoclax according to the 5-week ramp-up schedule. After finishing the ramp-up program on cycle 2 day 2, patients should continue taking 400mg once a day from cycle 3 day 1 until the conclusion of cycle 12.

Rituximab should be started after the patient has finished the fifth-week dose ramp-up regimen and received the 400mg dose of venetoclax for 7 days. For six cycles, provide rituximab intravenously on day one of each 28-day cycle, with a dose of 375 mg/m2 for cycle one and 500 mg/m2 for cycles two through six.

CONTRAINDICATIONS: 

Venetoclax should not be used together with powerful CYP3A inhibitors at the beginning or during the ram-up phase in patients with CLL/SLL because of the increased risk of tumor lysis syndrome.

DRUG INTERACTIONS:

Before taking venetoclax, consult your doctor about any medications you are already taking for other conditions. Some medications may interact with one another, resulting in harmful effects. Here are some medicines that interact with venetoclax.

• Posaconazole(Noxafil) or ketoconazole, is a medicine used for fungal infections.
• Ritonavir is commonly used to treat HIV.
• Rifampin is used to treat an infection called tuberculosis.
• Digoxin is used to treat irregular heartbeat and some types of heart failure.

FOOD INTERACTIONS:

Avoid eating grapefruits, oranges, marmalades, and starfruit, and do not drink juices of grapefruit, oranges, and starfruits.

ADVERSE EFFECTS:

• Throat infection
• Constipation
• Tiredness
• Neutropenia
• Diarrhea
• Anemia
• Thrombocytopenia
• Constipation
• Fever
• Muscle or joint pains
• Bleeding
• Stomach pain
• Dizziness
• Pneumonia
• Sepsis

TOXICITY:

Overdose of medication can lead to some toxic effects.

• Seizures
• Vomitings
• Difficulty in taking a breath.