Early development

Once a lead compound is selected for further evaluation, optimization and formulation, a series of investigations is undertaken to scrutinize its PK, PD, Toxicity and Efficacy properties. These investigations have to yield a clear picture of the PK-LADME (Liberation, Absorption, Degradation, Metabolism and Excretion), Toxicity and Pharmacology profile.

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At Atheris we put our expertise to work to help our partners in various stages of the drug development process. For instance, we undertake investigations that can be integrated in the:

• Lead optimization - Selectivity, solubility, stability, potency, ease of synthesis, metabolic stability against enzymes and membrane permeability.
  
  
• Pre-clinical studies - Pharmacokinetics, pharmacodynamics, biodistribution, clearance, toxicology, safety, pharmacology and drug metabolism studies in various models.
  
  
• Industrial evaluation - Medical needs, drugability, intellectual property, market studies and competitive technology survey.
  
  

Whether as part of a full study confided to Atheris or as a stand-alone service, we perform custom-designed and highly reliable investigations in several areas. This completes the lead discovery cycle of investigations and allows the selection of lead candidates for the early development stage of the drug discovery process.

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Lead optimization

Our original approach also includes the screening for natural analogues of selected lead compounds. In most cases, a lead compound will belong to a structural family, of which many analogues designed by Nature can be identified in similar samples. This allows drawing a map of analogues and identify key structural signatures and positions that undergo a higher rate of mutations. This information if of great assistance to drug design strategies, to give clues for lead optimization. Our approach is thus again based on parallel strategies and involves:

• Screening for natural analogues (in silico & in vitro).
  
  
• Structure-function studies (bio-computing loop).
  
  
• Structure-Activity-Relation (SAR) studies.
  
  
• Ease of production to reduce costs of goods.
  
  

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Stability assays

The stability of the lead compound is crucial. To evaluate this, we use HPLC and mass spectrometry for a sensitive follow-up, detection, identification and quantification of degradation products over time under various conditions.

• Stability of formulated product during storage and for administration.
  
  
• Quality control with identification and quantification of by-products.
  
  
• Preliminary stability testing under the conditions of sample preparation and storage.
  
  
• Stability following multiple freeze-thaw cycles.
  
  
• In vitro plasmatic stability with identification of degradation fragments.
  
  

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PK-LADME Pharmacokinetic and metabolic studies

Based on our analytical capacities, we also willingly assist early stage development, for example through:

• Pharmacokinetic and metabolic studies: PK-LADME (Liberation, Absorption, Distribution, Metabolism and Excretion).
  
  
• Identification of metabolites (in vitro & in vivo).
  
  
• Plasma half-life following administration.
  
  

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Again we can assist toxicity studies through an array of analytical studies:

• PK-LADME at low and high doses, short & long term.
  
  
• No-toxic-effect dose and maximal tolerated dose.
  
  
• Identification of potential organs of toxicity.
  
  
• Potential biochemical markers of toxic events.
  

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