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Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery
Chad L Stoner1, Adriaan Cleton, Kjell Johnson
1Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
International Journal of Pharmaceutics
|December 31, 2003
Summary
In vitro bioavailability estimation effectively predicts in vivo outcomes, enabling early drug candidate selection. This approach helps reduce attrition by identifying compounds with poor absorption, distribution, metabolism, and excretion (ADME) properties before costly in vivo testing.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Drug Discovery and Development
Background:
- Accurate prediction of in vivo bioavailability early in drug discovery is crucial for efficient lead candidate selection.
- Existing in vitro assays provide valuable data on absorption, distribution, metabolism, and excretion (ADME) properties.
Purpose of the Study:
- To evaluate the relationship between in vitro estimated bioavailability and in vivo observed bioavailability in preclinical models.
- To assess the utility of in vitro bioavailability estimations for selecting drug candidates in early-stage discovery.
Main Methods:
- Compiled in vitro ADME data (solubility, Caco-2 permeability, metabolic stability) and in vivo rat pharmacokinetic (PK) data for 140 diverse compounds.
- Calculated fraction dose absorbed (FDp) using the IDEA model and in vitro intrinsic clearance (CL(int)') from metabolic stability.
- Scaled in vitro clearance to predict in vivo clearance (CL) and hepatic extraction, then compared estimated (F(est)) with observed (F(obs)) bioavailability in rats.
Main Results:
- A strong correlation was observed between in vitro estimated bioavailability (F(est)) and in vivo measured bioavailability (F(obs)).
- Compounds with estimated in vitro bioavailability below 15% were highly likely to exhibit in vivo bioavailability below 30%.
Conclusions:
- In vitro bioavailability estimation is a reliable tool for predicting in vivo performance in drug discovery.
- Utilizing in vitro data allows for the early elimination of compounds with low bioavailability, reducing attrition rates due to poor ADME properties.