What is the pharmacology and mechanism of action of Venetoclax (Abbvie's Venclexta, generic name: Venetoclax)?

Pharmacology and Mechanism of Action of Venetoclax

Venetoclax is a potent, selective inhibitor of B-cell lymphoma-2 (BCL-2) protein that works by directly binding to BCL-2 and reinstating the apoptotic potential of cancer cells. 1, 2

Mechanism of Action

• Venetoclax is a BH3-mimetic that specifically blocks the anti-apoptotic B-cell lymphoma-2 (BCL-2) protein, resulting in programmed cell death of malignant cells 3
• By binding with high affinity to BCL-2, venetoclax displaces pro-apoptotic proteins (such as BIM, BAX, BAK), which then trigger the intrinsic apoptotic pathway in cancer cells 4
• BCL-2 overexpression is common in many hematologic malignancies, contributing to cancer cell survival and resistance to conventional therapies 2
• Venetoclax has demonstrated particular efficacy in malignancies with high BCL-2 dependence, such as chronic lymphocytic leukemia (CLL) and certain types of acute myeloid leukemia (AML) 5

Pharmacokinetics

• Venetoclax is metabolized primarily through the CYP3A4/5 enzyme pathway, making drug interactions with CYP3A inhibitors clinically significant 3
• When co-administered with strong CYP3A inhibitors (such as certain azole antifungals), venetoclax exposure increases significantly, requiring dose adjustments 3
• Specific dose reductions are recommended when venetoclax is combined with CYP3A inhibitors:
  • 75% dose reduction when combined with posaconazole 3
  • Dose adjustments are also needed with other CYP3A inhibitors such as erythromycin, ciprofloxacin, and other azole antifungals 3

Clinical Applications

• Venetoclax is FDA-approved for:
  • CLL/SLL in treatment-naïve patients (in combination with obinutuzumab) 6
  • Relapsed/refractory CLL (in combination with rituximab) 6
  • Newly diagnosed AML in adults ≥75 years or with comorbidities that preclude intensive chemotherapy (in combination with hypomethylating agents or low-dose cytarabine) 3
• Response rates vary by disease and genetic profile:
  • In CLL, venetoclax-based regimens have shown overall response rates of 79.4% in patients with high-risk features such as del(17p) 3
  • In AML, combination therapy with hypomethylating agents shows 67% complete remission or complete remission with incomplete count recovery 1

Dosing Considerations

• Gradual dose ramp-up is essential to mitigate tumor lysis syndrome (TLS) risk:
  • For CLL, starting at 20 mg with weekly escalation over 5 weeks to reach the target dose of 400 mg daily 3, 7
  • For AML, standard dosing is 400 mg daily in combination with hypomethylating agents 1
• Prophylactic measures during initiation include:
  • Aggressive hydration (oral and IV as needed) 7
  • Allopurinol or other uric acid-lowering agents started 2-3 days before venetoclax initiation 3, 7
  • Close monitoring of electrolytes and renal function 7

Adverse Effects

• Hematologic toxicities:
  • Neutropenia is common (40% grade 3-4) and may require growth factor support and/or dose adjustments 3
  • Thrombocytopenia (15%) and anemia (18%) are also reported 3
• Tumor lysis syndrome (TLS):
  • Rapid cancer cell death can lead to TLS, particularly in patients with high tumor burden 7
  • Risk is mitigated through gradual dose escalation, prophylaxis, and monitoring 3, 7
• Infections:
  • Increased risk of infections, particularly in combination therapy (84% of any grade) 3
  • Common infections include pneumonia, bacteremia, cellulitis, and urinary tract infections 3

Management of Toxicities

• For neutropenia:
  • Consider dose interruptions to allow for hematologic recovery 3
  • In patients with good response but persistent neutropenia, dose reduction in subsequent courses may be beneficial 3
  • Granulocyte colony-stimulating factor may be considered if dose reduction is ineffective 3
• For TLS:
  • Temporary hold of venetoclax and aggressive management of electrolyte abnormalities 7
  • Hospitalization may be required for high-risk patients during dose escalation 7

Drug Interactions

• Strong CYP3A inhibitors significantly increase venetoclax exposure:
  • Posaconazole: reduce venetoclax dose by 75% 3
  • Other azole antifungals, macrolides, and certain antibiotics (e.g., ciprofloxacin): ensure proper dose adjustments 3
• Alternative antifungals such as echinocandins may be preferred when venetoclax is used 3