Introduction

Ontologies are a representation of domain knowledge using defined concepts and the relationships between those concepts in a manner understandable to both humans and machines. However, this knowledge representation usually expresses a narrow, ideal situation, which might not reflect real-world complexities. Contextualization of the role concept (hereafter referred to as role) and role modelling provides a structured and modular way to capture these real-world complexities. In order to model how different regulatory contexts can affect the definition of the active moiety role, the general pattern for contextualized roles as shown in diagram 1 is applied to the examples for Amlodipine and Aripiprazole below.

Heiner Oberkampf  provide intro for what are roles and why we need them

substance constituency - constituency that defines some substance based on its relationship(s) to some other substance (ingredient) or moiety, potentially in some amount, in some context

Li Ming Gooi Break down into three different diagrams

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Diagram 1: General pattern for contextualized roles.

Role Hierarchy

The role (https://www.omg.org/spec/Commons/PartiesAndSituations/Role) is modeled as a class and can be specialized with sub-classes some of which are shown in the following diagram 2.

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Diagram 2: The role class and its specialized sub-classes.

Context Definition

The context is a "situation" or frame of reference in which something applies, exists, happens, or is used and that helps to illustrate or explain it. As with roles, contexts can be further specified with sub-classes as shown in Diagram 3.

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Diagram 3: Context and its sub-classes.

Examples

Modeling the active moiety role for Amlodipine bezylate in the regulatory context

Amlodipine bezylate is used here as a simple example to demonstrate the modeling pattern for contextualized roles, where Amlodipine plays the active moiety role for the drug Amlodipine bezylate in a regulatory context.

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Diagram 4: Modeling Amlodipine as the active moiety for Amlodipine bezylate in a regulatory context

Modeling the different active moiety roles for Aripiprazole lauroxil in different contexts

The contextualized role pattern is used here to model interpretations of the active moiety role for Aripiprazole in different situations. Aristada is a drug developed by Alkermes and is composed of Aripiprazole lauroxil. Aripiprazole lauroxil is first metabolized to N-hydroxymethyl aripiprazole, which is then further metabolized to Aripiprazole which exerts pharmaceutical effects in the body. From a regulatory perspective, Aripiprazole is thus the active moiety. However, based on the interpretation of a patent by the US court, based on the fillings by the owner of the intellectual property (IP) on Aripiprazole lauroxil, the active component is stated as the N-hydroxymethylated product instead. Diagrams 5 and 6 below demonstrate how in different contexts, the active moiety for Aripiprazole lauroxil can be either N-hydroxymethyl aripripazole or Aripiprazole itself.

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In the third example, the USP salt policy context is considered when naming the active moiety for Aripiprazole lauroxil. The USP (United States Pharmacopeia) Salt Policy outlines a naming and labeling approach for drug products containing an active ingredient that is a salt, and applies to drug product monograph titles published after the 1st of May 2013. According to the USP salt policy, Aripiprazole lauroxil is designated as the active moiety for Aripiprazole lauroxil (Diagram 7).

Moiety Role - N-hydroxymethyl aripiprazole - Patent Exclusivity

Diagram 5: Modeling N-hydroxymethyl aripiprazole as the active moiety for Aripiprazole lauroxil in a FDA patent exclusivity context

Moiety Role - Aripiprazole - Regulatory Context GSRS

Diagram 6: Modeling Aripiprazole as the active moiety for Aripiprazole lauroxil in a regulatory FDA GSRS context

Moiety Role - Aripiprazole - USP Salt Policy context

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USP documentation

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