title: A phase 1 randomized study evaluating the effect of omeprazole on the pharmacokinetics of a novel 5-hydroxytryptamine receptor 4 agonist, revexepride (SSP-002358), in healthy adults.
abstract: BACKGROUND
  About 30% of patients with gastroesophageal reflux disease continue to experience symptoms despite treatment with proton pump inhibitors. The 5-hydroxytryptamine 4 receptor agonist revexepride (SSP-002358) is a novel prokinetic that stimulates gastrointestinal motility, which has been suggested as a continued cause of symptoms in these patients. The aim of this study was to assess whether revexepride pharmacokinetics were affected by co-administration of omeprazole, in preparation for a proof-of-concept evaluation of revexepride added to proton pump inhibitor treatment.
  
  
  METHODS
  In this phase 1, open-label, randomized, two-period crossover study, healthy adults aged 18-55 years were given a single dose of revexepride 1 mg or revexepride 1 mg + omeprazole 40 mg. Pharmacokinetic parameters were assessed for up to 48 hours after administration of the investigational product. Adverse events, clinical chemistry and hematology parameters, electrocardiograms, and vital signs were monitored.
  
  
  RESULTS
  In total, 42 participants were enrolled and 40 completed the study. The median age was 24 years (18-54 years), 55% were women and 93% were white. The pharmacokinetic parameters of revexepride were similar without or with omeprazole co-administration. The mean area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) was 23.3 ng · h/mL (standard deviation [SD]: 6.33 ng · h/mL) versus 24.6 ng · h/mL (SD: 6.31 ng · h/mL), and maximum plasma concentrations (Cmax) were 3.89 ng/mL (SD: 1.30 ng/mL) and 4.12 ng/mL (SD: 1.29 ng/mL) in participants without and with omeprazole, respectively. For AUC0-∞ and Cmax, the 90% confidence intervals for the ratios of geometric least-squares means (with:without omeprazole) were fully contained within the pre-defined equivalence limits of 0.80-1.25. Mean apparent terminal phase half-life was 9.95 hours (SD: 2.06 hours) without omeprazole, and 11.0 hours (SD: 3.25 hours) with omeprazole.
  
  
  CONCLUSIONS
  Co-administration of the 5-hydroxytryptamine receptor 4 agonist revexepride with omeprazole did not affect the pharmacokinetics of revexepride in healthy adults.
authors.affiliation: Shire, Basingstoke, UK.
authors.forename: David
authors.initials: D
authors.lastname: Pierce
authors.affiliation: Shire, Wayne, PA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Corcoran
authors.affiliation: PRA International, Zuidlaren, the Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Velinova
authors.affiliation: Covance, Leeds, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hossack
authors.affiliation: Shire-Movetis NV, Turnhout, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Hoppenbrouwers
authors.affiliation: Shire, Wayne, PA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D000328:Adult; D001572:Benzofurans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001572:Benzofurans; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; C000600233:revexepride; D009853:Omeprazole
keywords: gastroesophageal reflux disease; omeprazole; pharmacokinetics; revexepride