Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling

Eur J Pharm Sci. 2017 Mar 30;100:42-55. doi: 10.1016/j.ejps.2016.12.017. Epub 2016 Dec 21.


The aim of this study was to optimize the in vitro transfer model and to increase its biorelevance to more accurately mimic the in vivo supersaturation and precipitation behaviour of weak basic drugs. Therefore, disintegration of the formulation, volumes of the stomach and intestinal compartments, transfer rate, bile salt concentration, pH range and paddle speed were varied over a physiological relevant range. The supersaturation and precipitation data from these experiments for Ketoconazole (KTZ) were coupled to physiologically based pharmacokinetic (PBPK) model using Stella® software, which also incorporated the disposition kinetics of KTZ taken from the literature, in order to simulate the oral absorption and plasma profile in humans. As expected for a poorly soluble weak base, KTZ demonstrated supersaturation followed by precipitation under various in vitro conditions simulating the proximal small intestine with the results influenced by transfer rate, hydrodynamics, volume, bile salt concentration and pH values. When the in vitro data representing the "average" GI conditions was coupled to the PBPK model, the simulated profiles came closest to the observed mean plasma profiles for KTZ. In line with the high permeability of KTZ, the simulated profiles were highly influenced by supersaturation whilst precipitation was not predicted to occur in vivo. A physiological relevant in vitro "standard" transfer model setup to investigate supersaturation and precipitation was established. For translating the in vitro data to the in vivo setting, it is important that permeability is considered which can be achieved by coupling the in vitro data to PBPK modelling.

Keywords: In vitro in vivo correlation (IVIVC); Ketoconazole; Physiologically-based pharmacokinetic (PBPK) model; Precipitation; Predicting drug absorption; Supersaturation; Transfer model.

MeSH terms

  • Antifungal Agents / blood
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacokinetics
  • Gastric Mucosa / metabolism
  • Humans
  • Intestinal Absorption
  • Intestine, Small / metabolism
  • Ketoconazole / blood
  • Ketoconazole / chemistry
  • Ketoconazole / pharmacokinetics*
  • Models, Biological*
  • Solubility


  • Antifungal Agents
  • Ketoconazole