Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin

Abstract

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate.

2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100  mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study.

3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (C_max) by 35% and area under the plasma-concentration time curve (AUC_0–∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Keywords:

• BCL-2
• CLL
• digoxin
• interactions
• P-glycoprotein
• pharmacokinetics
• venetoclax

Acknowledgements

The authors would like to thank Sonja Kemmis Causemaker, MEd, BS, an employee of AbbVie, for her medical writing support.

Declaration of interest

All authors are employees of AbbVie and may hold AbbVie stock or stock options. Venetoclax is being developed in collaboration between AbbVie and Genentech/Roche.

AbbVie and Genentech/Roche provided financial support for the studies and participated in the design, study conduct, analysis and interpretation of data as well as the writing, review and approval of the manuscript.