In-vitro Toxicity Testing

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In-vitro Toxicity Testing in Drug Development
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Toxicity Testing

• Before submitting an IND application, the
  concerned drug must go through a comprehensive
  series of in-vitro and in-vivo toxicity testing
  to ensure maximum safety in clinical trials.
• Considering the ethical issues and the cost of
  in-vivo animal tests, the pharmaceutical industry
  now relies more on in-vitro methods for toxicity
  testing in the drug development phase.

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Here, we answer the common questions regarding
the in-vitro toxicity testing in drug development.
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1) What is the right time to screen for toxicity
in drug discovery and development project?

• Screening for toxicity should start as early as
  possible to reveal inappropriate drugs early.
• This helps to eliminate such drugs from the drug
  development process timely and saves resources.

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2) What are the most common types of toxicity
observed in drug development?

• Hepatotoxicity (toxic effects on the liver) and
  cardiotoxicity (toxic effects on the heart) are
  the most severe problems encountered in drug
  development and the major reason for drug
  withdrawals.
• In addition, possible mutagenesis (genotoxicity)
  caused by the concerned drug candidates is also
  observed frequently.

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3) What types of assays are used for liver
toxicity testing?

• Liver toxicity or Drug-induced liver injury
  (DILI) can occur through several mechanisms like
  direct cell injury, mitochondrial injury, etc. To
  study direct cell toxicity, you can use membrane
  integrity assay (LDH release).
• The viability of the cells can be assessed by
  measuring cell metabolic activity using MTT assay
  or by measuring the ATP levels of the cells.

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4) How do you screen for cardiotoxicity?

• The severe cardiotoxic effect is mainly caused by
  the blockage of a potassium ion channel, hERG
  (human Ether-à-go-go-related gene) which prolongs
  the QT interval.
• Thus, cardiotoxic effects can be screened by
  testing the hERG blockage. They use HTS 384-plate
  fluorescence polarisation assay for this purpose
  as it is cost-effective and gives quicker results
  than the traditional patch-clamp assay.

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5) Why should you screen for genotoxicity?

• Genotoxic compounds can cause mutations in DNA
  and predispose to cancer and reproductive
  problems. Therefore, its crucial to screen for
  genotoxicity.
• As per the regulatory guidelines, the standard
  tests for genotoxicity screening include
  bacterial reverse mutation test (AMES) and a
  mammalian genotoxicity assay.

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6) What are the other toxicity tests to consider
in drug development?

• Based on the properties of the investigational
  drug, other screening assays to consider are
  reactive metabolite formation and time-dependent
  CYP inhibition or transporter inhibition.
• 3D cell models are useful o screen for
  metabolism-dependent toxicity or delayed toxicity
  as they allow long-term incubation with the
  metabolically active cells.

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7) What are the requirements of the authorities
for toxicity studies?
The safety of a new drug candidate is very
important. Therefore, toxicity testing is
strictly controlled and has to be performed in
animals and in GLP (Good Laboratory Practice)
conditions to select a safe starting dose for the
clinical trial in humans. Non-GLP screening
assays are not accepted any more. 
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