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
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.
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.
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.
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.
NOTE: The differences in interpretation of active moiety for Aripiprazole lauroxil came about, as Otsuka Pharmaceuticals challenged FDA's approval for a new drug application for Alkermes's drug Aristada (Aripiprazole lauroxil) stating that it ultimately metabolizes to Aripiprazole which is the active moiety for Otsuka Pharmaceutical's drug Abilify (Aripiprazole). However, under USP's salt policy, the active moiety for Aripiprazole lauroxil is designated as N-hydroxymethyl aripiprazole.
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
Diagram 7: Modeling Aripiprazole lauroxil as the active moiety for Aripiprazole lauroxil in a USP salt policy context