Metabolism and in vitro drug–drug interaction assessment of viloxazine

Abstract

1. Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the in vitro drug–drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations.

2. In vivo absorption-distribution-metabolism-excretion (ADME) studies demonstrated that in humans 5-hydroxylation followed by glucuronidation is the major metabolic route. This route was also seen as a minor route in rats where the major route is O-deethylation with subsequent sulfation.

3. In humans, the 5-hydoxylation pathway is mediated by CYP2D6. An estimate for the fraction of the metabolism via this pathway suggests a PM/EM difference of <2-fold, making it highly unlikely that this will be an issue of clinical significance.

4. Viloxazine forms a unique N-carbamoyl glucuronide in humans. The chemical reactivity characteristics of this metabolite are similar to stable glucuronide conjugates and dissimilar from acyl glucuronides; therefore, it is regarded as a stable Phase II conjugate.

5. In vitro drug–drug interaction (DDI) testing indicates that viloxazine is not a significant inhibitor or inducer of CYPs and transporters with the exception of CYP1A2.

Keywords:

• Viloxazine
• drug–drug interaction
• cytochrome P450
• ADHD
• absorption-distribution-metabolism-excretion (ADME)

Disclosure statement

Chungping Yu is an employee of Supernus Pharmaceuticals, Inc. The study was funded and conducted by Supernus Pharmaceuticals, Inc.

Additional information

Funding

This work was supported by the Supernus Pharmaceuticals, Inc.