Tuesday, September 26
Industry-Sponsored Symposium
Presented by Lonza

Direct and Quantitative Evaluation of CYP450 Contribution (fm) to Drug Clearance Using the in vitro Mod-el Silensomes™
Ashwani Sharma

The purpose of this presentation is to understand the role of the Silensomes™ to evaluate in vitro the fraction of the drug metabolized (fm) by each CYP in order to predict DDI. 

Regulators, including the U.S. Food and Drug Administration (FDA) have taken a prospective approach to the problem of drug interactions by assessing the interaction potential at an early stage of drug de-velopment. As a result, prediction of metabolically-based DDIs from in vitro and in vivo data has be-come a need in drug development. However, the accuracy of predicted results depends on the quality of the input dataset. In addition it is crucial that the complexities of the DDI process, as much as possible, are modeled in a well-defined algorithm based on fully reliable data.

In vitro identification and measurement of the contribution (fm) of the major cytochrome P450 enzymes (CYP450s) involved in the metabolism of a new drug candidate, also called “CYP450 phenotyping”, helps to predict the impact of other co-administered drugs (perpetrators) on the pharmacokinetics of the new chemical entity (NCE = victim). Today, a battery of in vitro tests (recommended by the regulatory agencies) is required for CYP450 phenotyping, each of which has a number of limitations.

A new in vitro model, called Silensomes™, has been developed to address the disadvantages of the current methodologies. Silensomes™ are human pooled HLM chemically and irreversibly inactivated for one specific CYP450 activity (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) using a mechanism based inhibitor (MBI). Examples of fm evaluation for NCE metabolized by one or several CYPs will be shown. Correlation between in vitro and in vivo fm evaluation will be demonstrated

Learning objectives of this session include evaluation of fm for the DDI prediction using a new in vitro tool, SilensomesTM.