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In vitro to in vivo extrapolation using Cloe HIA to understand site specific drug absorption and solve absorption issues

Simulate oral drug absorption from Caco-2 permeability and simple phys-chem data

  • Quantitatively predict human intestinal absorption from Caco-2 permeability and simple physicochemical data.
  • Understand dose-dependent absorption and ascertain whether solubility or permeability is limiting poor absorption.
  • Identify the main site of absorption within the gastrointestinal (GI) tract.
  • Solve problems such as poor absorption in the GI tract.
A tool for integrating in vitro ADME and phys-chem data to simulate dose dependent absorption in the GI tract.


How to use Cloe HIA

Cloe HIA data requirements for human intestinal absorption simulation

A simple set of early ADME and physicochemical data is required to run a Cloe HIA prediction as detailed below. Either measured or predicted values can be used.

Data requirements for Cloe HIA
  • Aqueous solubility at one or more pH (a discrete value or a solubility range can be provided at each pH)
  • Caco-2 apparent permeability coefficient (Papp) at a measured pH (apical to basolateral only)
  • pKa value(s)
  • Log P

Cloe HIA data delivery for understanding dose dependent drug absorption issues

Predictions are generated in a downloadable pdf report and Excel spreadsheet with interactive sensitivity analysis capability.

The following parameters are reported.

  • Predicted total absorption at several user-specified dose levels.
  • Identification of factors (solubility and/or permeability) limiting absorption at any poorly absorbed dose level(s).
  • Predicted dependence of the solubility on pH, over the range of the GI tract contents (pH 2-7.5).
  • Predicted absorption from the different segments of the GI tract at each dose level.
  • Predicted time course data representing absorption over time.
  • Predicted solubility over the pH range of the gastrointestinal tract, and the peak concentration of compound achieved in the different parts of the tract.

Using Cloe HIA to predict human intestinal absorption

Options for using Cloe HIA to predict human intestinal absorption

Additional Features
  • Interactive sensitivity analysis to investigate the impact of altering compound properties on the predicted human intestinal absorption.
  • Identifies the optimal pH values at which to measure the solubility of ionizable compounds.
  • Send your data to Cyprotex, and let us run predictions on your behalf.
  • Provision of full consultancy service for interpretation of any predictions generated.


Data from Cloe HIA for predicting human intestinal absorption

Cloe HIA uses physiological modeling to integrate Caco-2 permeability and phys-chem data. It models transit of fluid (containing dissolved and undissolved compound), gastric, biliary and pancreatic secretion and absorption in five segments of the GI tract.

Cloe HIA schematic diagram of the intestinal absorption model
Figure 1

Schematic diagram of the intestinal absorption model.

Nine compartments representing the five segments of the GI tract – stomach, duodenum, jejunum, ileum and colon – are represented. The fluid content, carrying dissolved and undissolved compound passes from one compartment to the next, simulating the action of peristaltic motion. Within each compartment the dynamic interconversion between dissolved and undissolved compound is modeled. Dissolved compound can be absorbed across the GI tract epithelium. The volume of each compartment – which represents the fluid content – is modeled dynamically, simulating the following processes:

• Transit of the fluid with characteristic rate constants through each compartment.
• Gastric secretion into the stomach, and biliary and pancreatic secretions into the duodenum.
• Absorption of fluid from duodenum, jejunum, ileum and large intestine.
Prediction of human intestinal absorption using Caco-2 permeability, turbidimetric solubility and pKa data combined with physiological modelling
Figure 2
Prediction of human intestinal absorption using Caco-2 permeability, turbidimetric solubility, pKa and logP data combined with physiological modeling.

The solid line represents the line of unity and the dotted line represent two fold of the reported fraction absorbed values. Data are for 122 combinations of dose and compound for 82 compounds. Reported values are from Thomas et al (2008). Cloe HIA provides a reliable quantitative prediction of human intestinal absorption from Caco-2 Papp, solubility, pKa and log P data. Greater than 84% of the predictions are within two-fold of the reported in vivo value for an independent test set (Figure 2) and the Spearman rank correlation coefficient between predicted and reported fraction absorbed is 0.76. It is a generic model which is applicable to a diverse set of chemistry. The model addresses dose-dependent absorption and the potential limitations of solubility on human intestinal absorption.
Gaining access to Cloe HIA
Cyprotex can run Cloe HIA predictions on your behalf. You can either send us your data or we can generate data for you via our in vitro ADME or phys-chem services. Assistance in interpreting the data is included in this service.

Contact for a demo


Thomas S et al. (2008) J. Pharm. Sci 97; 4557-74  

Cloe®is a registered trademark owned by Cyprotex PLC

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