Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin's Lymphoma.

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Salem AH, Agarwal SK, Dunbar M, Enschede SL, Humerickhouse RA, Wong SL

Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin's Lymphoma.

J Clin Pharmacol. 2016 Aug 25. doi: 10.1002/jcph.821.

PubMed ID
27558232 [ View in PubMed
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Abstract

Venetoclax is a selective BCL-2 inhibitor that is now approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors as well as low and high fat meals on venetoclax pharmacokinetics. Patients received a once daily venetoclax dose of 20 mg to 1200 mg. Pharmacokinetic parameters were estimated using non-compartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low fat conditions and the mean terminal phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold, relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60% while weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax. This article is protected by copyright. All rights reserved.

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