⚙️🌎CPCA: the gestation, birth, and development -Pub

This is one of those articles that delves into the behind-the-scenes of science. You will be able to follow the gestation, birth, and development of CPCA. Check out this article:

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it covers the entire birth of CPCA. Here is a general analysis:

  1. Introduction:
  • The article describes the approach of CPCA, a structure-activity relationship methodology adopted in 2023 for international regulatory guidance on assessing the safety of nitrosamine impurities in pharmaceutical products.
  • CPCA utilizes structure-activity relationships to determine acceptable intake limits for nitrosamine impurities in pharmaceutical products.
  1. Development of CPCA:
  • An international Nitrosamine Working Group (NITWG) was established to develop CPCA, involving experts in pharmacology, toxicology, chemistry, computational toxicology, and structure-activity relationships.
  • The goal was to create a methodology that didn’t rely on robust data for a single surrogate compound in each Acceptable Intake (AI) assessment, allowing AI identification even when specific compound data isn’t available.
  • CPCA builds upon previously published works and an evaluation of structure-activity relationships from a larger dataset of nitrosamine carcinogenicity.
  1. Dataset and Model Development:
  • The training dataset included 81 nitrosamines with carcinogenicity data.
  • Activating and deactivating structural characteristics of carcinogenic potency were identified, used to assign a Potency Category (PC) to each nitrosamine.
  • Potency categories range from 1 (high potency) to 5 (low potency), with thresholds defined based on regional AI limits and toxicological concern limit for mutagenic impurities.
  1. Application of CPCA:
  • CPCA allows consideration of the relative effects of multiple activating and deactivating characteristics on the molecule to predict carcinogenic potency and recommend an AI limit.
  • Examples of applying CPCA to hypothetical impurity structures related to the active substance (NDSRIs) are provided in regulatory guidance.
  • The applicability domain of CPCA is limited to compounds with a carbon atom directly linked to both sides of the N-nitroso group.
  1. Conclusions:
  • CPCA serves as a practical tool to quickly determine recommended AI limits for nitrosamines based on structural characteristics.
  • Further development of CPCA will be facilitated by the availability of new experimental mutagenicity testing data and metabolism studies.
  • CPCA was developed to address situations where there were insufficient carcinogenicity data or where a structure-activity relationship assessment did not identify a suitable surrogate for cross-reading assessment.

Kudos to the authors!

Link: https://www.sciencedirect.com/science/article/pii/S0273230024000813

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By @jbercu

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Swiss medic referred the paper on its website. :grinning:

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I think it is quite innovative but still needs to be confirmed by experiments. I wish that at least 10 NDSRIs were subjected to carc. testing to confirm that what is being proposed by CPCA is close to what the AIs are.

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Looking forward to seeing this go in print and accessing the supplementary data as well.

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This paper is in print now, so the supplementary tables with more listed compounds considered during CPCA design is accessible on the publisher website now.

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