Gastrointestinal and Systemic Monitoring of Posaconazole in Humans After Fasted and Fed State Administration of a Solid Dispersion

J Pharm Sci. 2016 Sep;105(9):2904-2912. doi: 10.1016/j.xphs.2016.03.027. Epub 2016 May 10.

Abstract

The purpose of this study was to explore the intraluminal behavior and systemic exposure of posaconazole in humans after oral intake of a novel delayed-release tablet (Noxafil(®)), containing posaconazole dispersed in a matrix of hydroxypropyl methylcellulose acetate succinate. Five healthy volunteers were asked to ingest the tablet in the fasted and fed state condition, after positioning one aspiration catheter in the stomach and one in the jejunum. Subsequently, gastric and jejunal fluids were aspirated and analyzed for posaconazole. In parallel, blood samples were collected. In gastric aspirates, dissolved concentrations were negligible regardless of the test condition, confirming the delayed-release properties of the tablet. In fasted state jejunal aspirates, sustained supersaturation was observed during an average period of time of 93 ± 78.2 min, with a mean maximum degree of supersaturation of 7.28 ± 8.81. In the fed state condition, supersaturation was negligible in the jejunum with a pronounced presence of solid posaconazole, suggesting the importance of more distal intestinal regions for posaconazole absorption.

Keywords: absorption; amorphous; biopharmaceutics classification system; clinical pharmacokinetics; gastrointestinal; intestinal absorption; oral absorption; precipitation; solid dispersion; supersaturation.

MeSH terms

  • Adult
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics*
  • Body Fluids / chemistry
  • Body Fluids / metabolism
  • Catheterization
  • Cross-Over Studies
  • Delayed-Action Preparations
  • Drug Compounding
  • Duodenum / metabolism
  • Fasting
  • Female
  • Food-Drug Interactions
  • Gastric Mucosa / metabolism
  • Gastrointestinal Tract / metabolism*
  • Healthy Volunteers
  • Humans
  • Intestinal Absorption
  • Jejunum / metabolism
  • Male
  • Triazoles / analysis
  • Triazoles / pharmacokinetics*
  • Young Adult

Substances

  • Antifungal Agents
  • Delayed-Action Preparations
  • Triazoles
  • posaconazole