Pharmacokinetics, absorption, and excretion of radiolabeled revexepride: a Phase I clinical trial using a microtracer and accelerator mass spectrometry-based approach

Abstract

Purpose

Gastroesophageal reflux disease involves the reflux of gastric and/or duodenal content into the esophagus. Prokinetic therapies, such as the selective 5-hydroxytryptamine receptor 4 agonist revexepride, may aid gastric emptying. This Phase I study evaluated the pharmacokinetics and excretion pathways of [¹⁴C]revexepride in healthy individuals using a microtracer approach with accelerator mass spectrometry.

Participants and methods

Six healthy men received a single oral dose of 2 mg [¹⁴C]revexepride containing ~200 nCi of radioactivity; blood, urine, and fecal samples were collected over a 10-day period.

Results

Almost 100% of ¹⁴C was recovered: 38.2%±10.3% (mean ± standard deviation) was recovered in urine, and 57.3%±0.4% was recovered in feces. Blood cell uptake was low, based on the blood plasma total radioactivity ratio of 0.8. The mean revexepride renal clearance was 8.6 L/h, which was slightly higher than the typical glomerular filtration rate in healthy individuals. Time to reach maximal concentration was 1.75±1.17 hours (mean ± standard deviation). No safety signals were identified.

Conclusion

This study demonstrated that revexepride had rapid and moderate-to-good oral absorption. Excretion of radioactivity was completed with significant amounts in feces and urine. Renal clearance slightly exceeded the typical glomerular filtration rate, suggesting the involvement of active transportation in the renal tubules.

Keywords:

• accelerator mass spectrometry
• gastroesophageal reflux disease
• pharmacokinetics
• revexepride
• 5-hydroxytryptamine receptor 4 agonist

Acknowledgments

Robert Gillies, PhD, and Luci Witcomb, PhD, from PharmaGenesis, London, UK, provided editorial assistance for this manuscript, funded by Shire. The authors would also like to thank Lynne Poole and Patrick Martin of Shire for their assistance in preparing the manuscript, and the study participants for their involvement in the study.

Disclosure

The study was funded by Shire International GmbH, Eysins, Switzerland. Covance Laboratories Inc. was funded by Shire to conduct the clinical trial. Xceleron Inc was funded by Shire to perform AMS and LC–MS/MS analysis. PharmaGenesis London, UK, was funded by Shire to provide editorial assistance with the preparation of manuscript. Steven Troy and Jay Getsy are employees of Shire and also hold stocks/share options in Shire and report no other conflicts of interest in this work. Ron Budhram, Mike Pennick, and Graeme Scarfe are former employees of Shire and report no other conflicts of interest in this work. Stephen Flach, Marie Croft, Jie Ding, and Todd Pankratz report no conflicts of interest.