Absorption, distribution, metabolism and excretion of ¹⁴C-vatiquinone in rats, dogs, and human subjects

Abstract

1. Vatiquinone is a potent inhibitor of 15-lipoxygenase and is in clinical development for the treatment of mitochondrial diseases and other disorders characterised by high levels of oxidative stress and dysregulation of energy metabolism.

2. In rats, ¹⁴C-vatiquinone-derived radioactivity was quickly and widely distributed throughout the body and cleared from most tissues by 24 h post-dose following a single oral dose of ¹⁴C-vatiquinone.

3. Following oral administration, 94% of dose was recovered within seven days in rats, approximately 61% of dose was recovered within seven days in dogs and approximately 93% of dose was recovered within nine days in human subjects (IND 119220). Faecal excretion was the major route (>56% dose) in all species; urinary excretion was minimal in rats and dogs (<3% dose) but was higher in humans (∼ 22% dose).

4. Following oral administration, vatiquinone was the dominant circulating component in rats and dogs but was minor in human subjects. There were no plasma metabolites that were more than 10% of total drug related exposures in all species.

5. Following oral administration, vatiquinone was not detectable in urine but was the most prominent component in faeces in rats, dogs, and humans.

Keywords:

• Vatiquinone
• PTC743
• absorption
• distribution
• metabolism
• excretion

Author contributions

Ma J., Lee L., Yao B., Giannousis P., Thoolen M., Golden L., Klein M., and Kong R. participated in the research design. Ma J., Lee L., Ye Q., and Kong R. conducted experiments, performed data analysis and wrote or contributed to the writing of the manuscript.

Disclosure statement

All authors are current employees except that Thoolen M. is a former employee of PTC Therapeutics, Inc. Parts of this work were previously presented at a poster session of the American Epilepsy Society Annual Meeting; December 2–6. Nashville, Tennessee (Lee, et al. 2022).

Additional information

Funding

The study was sponsored by PTC Therapeutics, Inc.