Population In Vitro-In Vivo Correlation Model Linking Gastrointestinal Transit Time, pH, and Pharmacokinetics: Itraconazole as a Model Drug

Ahmad Y. Abuhelwa, Stuart Mudge, David Hayes, Richard N. Upton, David J.R. Foster

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract


Purpose: To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption. Methods: IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM. Results: Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a ‘Shiny’ application. Conclusion: An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.

Original languageEnglish
Pages (from-to)1782-1794
Number of pages13
JournalPHARMACEUTICAL RESEARCH
Volume33
Issue number7
DOIs
Publication statusPublished - Jul 2016
Externally publishedYes

Keywords

  • in vitro- in vivo correlation
  • itraconazole
  • NONMEM
  • population pharmacokinetic

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