Example: Terlipressin - REVIEW
- Heiner Oberkampf
- Elisa Kendall
- Li Ming Gooi
Disclaimer
This example is for illustration purposes only. The data provided may not be up-to-date, and in some cases, 'dummy' data has been included. The product information included here shall not be used for any other purpose than for educational purposes regarding the IDMP-O implementation.
Introduction
Terlipressin is a synthetic analogue of vasopressin, a hormone which regulates blood pressure and water retention in the body. It is approved among others for the therapeutic indication bleeding oesophageal varices in Europe. However, national regulatory requirements, history heritage or differences in the way the Summary of Product Characteristics (SmPC) or Patient Information Leaflet (PIL) are edited lead to different expressions of strength across EU countries for the same product. There is therefore, a perceived difference between products, within these markets. In the case of cross-border medicinal product information, products are perceived as different, leading to unnecessary questions, errors or rejections of the prescription. The details of Terlipressin as produced by SUN Pharmaceuticals and marketed in the European countries of United Kingdom, Sweden, and Netherlands are used here to demonstrate how the reference strength* of a pharmaceutical product can be depicted differently in different regions, and how the ontology model is then expanded to accommodate this complexity (further information can be obtained at https://github.com/edmcouncil/idmp/tree/master/EXT/Examples). The tables and figures below summarize the information obtained from the different SmPCs, PILs and Dossiers of Terlipressin as marketed by SUN Pharmaceuticals. In all instances, the same product is manufactured and sold. However they are presented differently in different countries.
Figure 1 Details modeled in the ontology for Terlipressin as manufactured by SUN Pharmaceuticals. This example highlights the need for representation of basis of strength according to geographical region and jurisdiction to prevent confusion about pharmaceutical products**. Specific details are further shown in the tables and model diagrams below.
Table 1 Comparison of strength expressions in the different labels for Terlipressin from SUN Pharmaceuticals marketed in Europe. The following table shows how confusion or ambiguity can arise from the use of different labels, although in the end they might essentially mean the same thing. Terlipressin diacetate pentahydrate is the actual substance manufactured for which the active moiety is Terlipressin. As 1 molecule of Terlipressin diacetate pentahydrate gives rise to 1 molecule of Terlipressin, the number of moles are thus similar, with only slight differences in the decimal value. It should be noted that 1 ampoule contains 8.5 ml. Multiplying the number of moles in the concentration strength by 5 would give rise to approximately the same number of moles for the presentation strength demonstrating equivalency.
| Substance | Molecular Weight | Type of strength | Strength | Number of moles |
|---|---|---|---|---|
Terlipressin | 1227.39 g/mol | Presentation Strength (Pr. Str.) | 0.85 mg/1 ampoule | 6.93 x 10-7 moles/ 1 ampoule |
| Terlipressin diacetate pentahydrate | 1437.55 g/mol | Presentation Strength (Pr. Str.) | 1 mg/1 ampoule | 6.95 x 10-7 moles/ 1 ampoule |
| Terlipressin | 1227.39 g/mol | Concentration Strength (Con. Str.) | 0.1 mg/1 ml | 8.14 x 10-8 moles/ 1 ml |
| Terlipressin diacetate pentahydrate | 1437.55 g/mol | Concentration Strength (Con. Str.) | 0.12 mg/1 ml | 8.34 x 10-8 moles/ 1 ml |
Table 2 Comparison of Strength expression in Europe. The following table provides details for how Terlipressin is depicted in the SmPC for the markets in which they are presented. Text highlighted in blue represent information obtained from the product Dossier, which provide additional information. (BoSS: Basis of Strength Substance, refers to the active ingredient or active moiety in a drug product that is measured to provide the product strength)
UK | Sweden | Netherlands | |
Product Name | Terlipressin acetate SUN 0.12 mg/ml solution for injection | Terlipressin SUN 1 mg solution for injection | Terlipressin SUN 0.1 mg/ml solution for injection |
Substance | Terlipressin acetate | Terlipressin acetate | Terlipressin acetate |
Strength | 1mg/1 ampoule | 1mg/1 ampoule | 1mg/1 ampoule |
Ref. Str. (1) Basis of Strength (Substance as manufactured) | Terlipressin acetate (BoSS) Pr. Str: 1 mg/1 ampoule Con. Str. 0.12 mg/1 ml (BoSS) | Terlipressin acetate (BoSS) Pr. Str: 1 mg/1 ampoule (BoSS) Con. Str. 0.12 mg/1 ml | Terlipressin acetate Pr. Str: 1 mg/1 ampoule Con. Str. 0.12 mg/1 ml |
Ref. Str. (2) (Active moiety) | Terlipressin Pr. Str: 0.85 mg/1 ampoule Con. Str. 0.1 mg/1 ml | Terlipressin Pr. Str: 0.85 mg/1 ampoule Con. Str. 0.1 mg/1 ml | Terlipressin (BoSS) Pr. Str: 0.85 mg/1 ampoule Con. Str. 0.1 mg/1 ml (BoSS) |
Table 3 Corrected presentation – Alignment based on Dossiere. The following shows instead how the information for Terlipressin could be more efficiently and uniformly depicted to prevent confusion
UK | Sweden | Netherlands | |
Name | Terlipressin acetate SUN 0.12 mg/ml solution for injection | Terlipressin SUN 1 mg solution for injection | Terlipressin SUN 0.1 mg/ml solution for injection |
Substance (INN Name) | Terlipressin acetate | Terlipressin acetate | Terlipressin acetate (SmpC) |
Strength | 1mg/1 ampoule | 1mg/1 ampoule | 1mg/1 ampoule |
Strength = ACTIB | Terlipressin acetate (INN) Pr. Str: 1 mg/1 ampoule Con. Str. 0.12 mg/1 ml | Terlipressin acetate Pr. Str: 1 mg/1 ampoule Con. Str. 0.12 mg/1 ml | Terlipressin acetate Pr. Str: 1 mg/1 ampoule Con. Str. 0.12 mg/1 ml |
Reference Strength = ACTIM (Active moiety) | Terlipressin Pr. Str: 0.85 mg/1 ampoule Con. Str. 0.1 mg/1 ml | Terlipressin Pr. Str: 0.85 mg/1 ampoule Con. Str. 0.1 mg/1 ml | Terlipressin (Reference subst) Pr. Str: 0.85 mg/1 ampoule Con. Str. 0.1 mg/1 ml |
Related Competency Questions
UC1 CQ02 What is the active moiety of <substance y>?
UC1 CQ03 What are the products that contain substances with common active moiety <active moiety x>?
UC1 CQ03.1 What is the basis of strength for <substance x> in <product y>?
UC1 CQ06 Which investigational/ authorized medicinal products contain the substance x and active moiety?
UC1 CQ07 Which manufactured items contain substance <x> as ingredient of type "active"?
Model Pattern Instantiation
The first competency question, what is the active moiety of <substance y>, is exemplified in Figure 2. The figure shows the substance, terlipressin acetate (terlipressin diacetate pentahydrate0, which contains terlipressin as its active moiety.
Figure 2. Diagram showing the active moiety pattern, including various properties that can be used for question answering.
Secondly, in order to demonstrate the second competency question, "what products have a given active moiety in common", we need to incorporate the concept of a pharmaceutical product as well as its composition, and connect the elements in the composition to its active moiety(ies). Figure 3 extends the patterns shown in Figure 2 to cover the additional concepts for a single product (Terlipressin Acetate SUN - pharmaceutical product) and its active ingredient (terlipressin acetate).
Figure 3. Diagram showing the relationships between a product, its composition, and the active moiety of one of the substances it is composed of.
In the Terlipressin case, there are multiple representations possible for representing the competency question, "What is the basis of strength for <substance x> in <product y>?", for which we depend on the definition of reference substance / reference strength, depending on the jurisdiction, as shown in the figures, below.
Figure 4 Diagram modeling Terlipressin SUN 0.1 mg/ml solution for injection as marketed in Netherlands
Note that some of the strength-related details, including numerator and denominator values, have been elided to simplify the diagram. They are present in the example ontology however. The *** on the property 'is applicable in jurisdiction' indicates that the line on the diagram is a property chain representing a short cut in the ontology for a broader pattern.
Figure 5 Diagram modeling Terlipressin Acetate SUN 0.12 mg/ml solution for injection as marketed in the United Kingdom of Great Britain and Norther Ireland (the)
Again, some of the strength-related details, including numerator and denominator values, have been elided to simplify the diagram. They are present in the example ontology however. The *** on the property 'is applicable in jurisdiction' indicates that the line on the diagram is a property chain representing a short cut in the ontology for a broader pattern.
* For a more detailed description on reference strength, please refer Pattern: Representing Reference Substances, Reference Strength, and the Basis of Strength, including in Different Jurisdictions - APPROVED
** Figures were modified from https://www.exportersindia.com/product-detail/finished-product-terlipressin-injection-3409913.htm, https://en.wikipedia.org/wiki/Terlipressin and https://www.clipartmax.com/middle/m2i8H7Z5G6N4K9H7_industrial-clipart-3d-factory-plant-icon/