Silensomes

Silensomes? - A ready-to-use in-vitro model for phenotying studies

Silensomes™ are human pooled liver microsomes in which one specific CYP has been chemically knocked out. Silensomes™ is a single unique and representative model, capable of directly quantifying and predicting the contribution of CYP enzymes in drug metabolism

Drug-drug interaction can significantly impact drug safety and efficacy. Prediction of this risk of drug-drug interactions is a requisite in the development of a new drug candidate and the submission of the registration dossier. In-vitro identification and measurement of the contribution of the major cytochrome P450 enzymes involved in the human metabolism of a new drug candidate, also called “CYP phenotyping”, helps predict the impact of co-administered drug(s) (perpetrator(s)) on the pharmacokinetics of the new chemical entity (victim).

Until now, a battery of in-vitro tests recommended by the regulatory agencies (EMA/FDA) is required for this CYP phenotyping assay. These tests (correlation analysis, antibody or chemical inhibition and metabolism by recombinant human enzymes) have a number of disadvantages:

  • No direct quantitative measurement of the contribution of each CYP in the metabolism of a drug (correlation analysis)
  • Model is not fully representative of the liver enzyme profile (e.g. human recombinant CYP450)
  • Lack of specificity (e.g. anti-CYP antibodies and chemical inhibitors)

To overcome the disadvantages of the current methodologies, Biopredic International has developed in collaboration with Servier Laboratories a patented new in-vitro drug development model

Silensomes™ are validated human pooled liver microsomes (HLMs) chemically and irreversibly inactivated for one specific CYP using mechanism based inhibitors (MBI). 

Each Silensomes™ is available as ready-to-use HLMs chemically knocked-out for one specific CYP activity (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) with each showing high specificity and efficiency of their targeted CYP inhibition (>80%), and only minor impact (<20%)

Key Advantages of Silensomes™:

Silensomes™: the model of choice for determination of the CYP contribution all along the development plan of a new chemical entity

  • Irreversibly inhibited CYPs
  • For initial rate conditions
  • For saturating conditions
  • One single model for CYP phenotyping assays, instead of a battery of in-vitro tests
  • Quantitative: the true contribution of the CYP450 in the metabolism of the coumpound can be measured
  • A powerful model with an excellent specificity, potency, stability and predictability to ensure reliable extrapolation of the drug-drug interaction risk
  • More representative of in-vivo, using human liver microsomes rather than recombinant enzymes isolated from non-mammalian cells

Silensomes™ are available for compound screening purposes and also for regulatory validation

 

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