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.

With the IDMP Ontology, we can express statements about things such as substances or medicinal products. While some statements are universally true (e.g., "Amlodipine is a chemical substance" or "Amlodipine is included in Norvasc") others are true only in specific situations/contexts, e.g., the "strength of Amlidipine" makes sense only in the context of a product.

To capture the context, an established pattern in ontology modelling is to use "roles". E.g., a human Max can play the role "patient" in the context of a treatment. Or a substance can play the role "active ingredient" in the context of one pharmaceutical product while the same substance may play the role "excipient" in the context of a different product.

The role concept (hereafter referred to as 'role') and corresponding ontological role model pattern provide a structured and modular way to capture many different real-world complexities.

Universal Statement (NO Role usage)

Example: Amlodipine Besylate is included in Norvasc pharmaceutical product

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Basic Role Pattern

Example: Amlodpine Besylate plays role active ingredient in Norvasc

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Roles and Constituents (Product Compositions)

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

More complex case where the constiuency of some substance or product is contingent on something, or for mixtures where there are amounts and other details in some context

Role Hierarchy in IDMP-O

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 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

USP documentation

USP Salt Policy (December 2014) - YouTube