Is dose adjustment of venetoclax (Venetoclax) necessary when co-administered with posaconazole (Posaconazole)?

From the Guidelines

Dose adjustment of venetoclax is necessary when co-administered with posaconazole, with a recommended reduction of venetoclax dose by 75%. This recommendation is based on the guidelines provided by the European Conference on Infections in Leukemia (ECIL) 1. The adjustment is crucial because posaconazole is a strong CYP3A inhibitor that can significantly increase venetoclax plasma concentrations, potentially leading to increased toxicity, particularly tumor lysis syndrome.

Key Considerations

• The dose reduction is essential to minimize the risk of adverse effects associated with elevated venetoclax levels.
• For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, the dose should be reduced to 70 mg or less when used with posaconazole.
• During the ramp-up phase, the dose should be reduced to 10 mg on day 1, followed by 20 mg on day 2, then 50 mg on day 3, and 70 mg on day 4 and beyond.
• Close monitoring for toxicity is essential even with dose reduction.
• If posaconazole must be discontinued, the normal venetoclax dosing should not be resumed immediately but rather after a washout period of 5-7 days, with close monitoring when returning to the standard dose.

Rationale

The recommendation for dose adjustment is based on the pharmacokinetic interaction between venetoclax and posaconazole. Venetoclax is metabolized by CYP3A4/5, and posaconazole is a strong inhibitor of this enzyme. The concomitant use of these drugs can lead to increased venetoclax plasma concentrations, which may result in increased toxicity. The ECIL guidelines provide evidence-based recommendations for managing this interaction, emphasizing the importance of dose adjustment to ensure patient safety 1.

Clinical Implications

The dose adjustment of venetoclax when co-administered with posaconazole has significant clinical implications. It highlights the need for careful consideration of drug interactions in patients receiving venetoclax, particularly those with compromised renal or hepatic function. Healthcare providers should be aware of the potential for increased toxicity and take steps to minimize this risk, including close monitoring of patients and adjustment of venetoclax doses as needed. By following these guidelines, clinicians can optimize the safety and efficacy of venetoclax therapy in patients with leukemia or other conditions requiring antifungal prophylaxis.

From the FDA Drug Label

7.16 Venetoclax Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax C maxand AUC 0-INF, which may increase venetoclax toxicities [see Contraindications (4. 6), Warnings and Precautions ( 5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

Dose adjustment is necessary when co-administering venetoclax with posaconazole, as posaconazole increases venetoclax exposure, which may increase the risk of venetoclax toxicities. The specific dosing instructions can be found in the venetoclax prescribing information 2.

From the Research

Dose Adjustment of Venetoclax with Posaconazole Co-administration

• The co-administration of venetoclax with posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor, requires dose adjustment of venetoclax to manage potential interactions 3, 4.
• A study published in 2017 found that co-administration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmax and AUC0-24 by 53% and 76%, respectively, whereas co-administration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC0-24 by 93% and 155%, respectively 3.
• Another study published in 2021 used physiologically based pharmacokinetic (PBPK) models to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically, and found that posaconazole increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range 4.
• The results of these studies suggest that dose adjustment of venetoclax is necessary when co-administered with posaconazole, with a recommended dose reduction of at least 75% 3 or to 70 mg in the presence of posaconazole at doses up to 500 mg QD 4.
• Therapeutic drug monitoring (TDM) is expected to guide drug dosage adjustments in patients receiving venetoclax and posaconazole co-administration, with the goal of achieving optimal venetoclax concentrations while minimizing the risk of adverse events 5.

Clinical Implications

• Close monitoring of posaconazole levels in venetoclax-treated patients is critical to ensuring adequate mould prophylaxis and preventing breakthrough invasive fungal infections 6.
• The co-administration of venetoclax and posaconazole requires careful consideration of the potential risks and benefits, as well as close monitoring of patients for adverse events and therapeutic responses 7, 5.
• The use of TDM and PBPK models can help guide dose adjustments and optimize the safety and efficacy of venetoclax and posaconazole co-administration in patients with acute myeloid leukemia and other hematological malignancies 4, 5.