Exploring pharmacoepidemiologic groupings of drugs from a clinical perspective

1. Medinfo 2013 Copenhagen, Denmark Session: Data models and representations - II August 21, 2013 Exploring pharmacoepidemiologicgroupingsof drugs from a clinical perspective Rainer Winnenburg, Olivier Bodenreider Lister Hill National Centerfor Biomedical CommunicationsBethesda, Maryland - USA

2. Motivation • Anatomical Therapeutic Chemical (ATC) classification • Used in pharmacoepidemiologic studies • Recently also used in applications from a clinical perspective • Assumes homogeneity of drug groups (in terms of therapeutic use, mechanism of action, physiologic effect) • BUT: “Substances classified in the same ATC fourth level cannot be considered pharmacotherapeuticallyequivalent since their mode of action, therapeutic effect, drug interactions and adverse drug reaction profile may differ.”(ATC documentation)

3. Objectives • To investigate the extent to which pharmacoepidemiologic groupings are homogeneous in terms of clinical properties • Pharmacoepidemiologicgroupings • ATC classification WHO • For comparison: Micromedex • Clinical properties • National Drug File-Reference Terminology (NDF-RT) • Homogeneity • Distribution of clinical properties of drugs within a grouping

4. Anatomical Therapeutic Chemical (ATC)drug classification • Hierarchical classification • Levels 1-4: drug groups (~ pharmacologic classes) • 1,255 drug group codes • Level 5: individual drugs • 4,464 drug codes (as of 2012)

5. National Drug File-Reference Terminology (NDF-RT) • Organized into several hierarchies • 7,162 active moieties (level = ingredient) • Relations to entities from other hierarchies • e.g., has_MoA relationships to mechanism of action hierarchy • We used NDF-RT API for • Mapping drug names from ATC to NDF-RT • Querying drug properties

6. Methods Overview • Mapping ATC drugs to ingredients in NDF-RT and acquiring clinical properties for ingredients • Computing homogeneity scores for each drug class based on properties of drugs in class • Comparison to the clinical reference Micromedex

7. Step 1 Mapping ATC drugs to clinical properties Eligibility ATC Drugs 5th level ATC Drugs (single ingredients within scope) • Exclude: • Multi-ingredient drugs • Radiopharmaceuticals • Unspecific, collective terms Prednisolone (R01AD02) Prednisolone (R01AD02) Lexical mapping and via RxNorm Relationships Clinical Properties (any of the 3 categories) NDF-RT Ingredients PREDNISOLONE (N0000146334)

8. Step 2 Computing homogeneity scores (classes) • Grouping Drugs ingrouping+ Clinical Properties 3 distinct properties HomogeneityScore How many distinct properties (or sets of properties) are necessary to account for at least 90% of the drugs in a given subgroup? • 1 property accounts for 2 drugs (66% of the drugs) • 2 properties account for all 3 drugs (>90% of the drugs) • => Homogeneity score = 2

9. Step 2 Homogeneity scores Examples Example 1: homogeneous group • ATC 4th level group Corticosteroids (R01AD) • 10 drugs • All 10 drugs have the same mechanism of action: Glucocorticoid Receptor Antagonists • One single property accounts for 100% of the drugs in this group => homogeneity score =1

10. Step 2 Homogeneity scores Examples Example 2: heterogeneous group • ATC 4th level group Antidotes (V03AB) • 12 drugs • 8 mechanism of action properties are needed to account for > 90% of the drugs in this group Siderophore Iron Chelating Activity, Cholinesterase Inhibitors, GABA B Antagonists, Free Radical Scavenging Activity, Alcohol Dehydrogenase Inhibitors, {Noncompetitive Opioid Antagonists, Competitive Opioid Antagonists}, {Adrenergic alpha1-Antagonists, Adrenergic alpha2-Antagonists}, and Cholinesterase Reactivators. => homogeneity score =8

11. Step 3 Comparison to a clinical reference • Clinical reference: drug groupings in Micromedex • Extracted from a drug-drug interaction system • Distribution of homogeneity scores (“profiles”) in ATC and Micromedex • 3 profiles • Therapeutic group • Mechanism of action • Physiologic effect • Hypothesis: if ATC is less homogeneous than Micromedex, it should have greater scores

12. 53% of 2nd level groups in ATC have homogeneity score of 1 or 2 vs. 75% for Micromedex ATC therapeutic (2nd level) groups less homogeneous than groups in Micromedex Therapeutic group profile

13. > 60 % of 4th level groups in ATC have homogeneity score of 1 Homogeneity of ATC groups comparable to that of groups in Micromedex Profiles for mechanism of action (MoA) and physiologic effect (PE)

14. Limitations and future work • Only 50% of single drugs in ATC could be mapped to NDF-RT properties • Some drugs are out of scope, not marketed in the U.S. • Incompleteness of NDF-RT in terms of drug properties • No statistical methodology used for the comparison of homogeneity distributions • We plan to explore alternative drug information sources for evaluation of ATC • Only few reliable and publicly available (e.g., DrugBank) • Most are commercial products (e.g., First Databank)

15. Summary • Investigated homogeneity of pharmacoepidemiologicgroupings in terms of clinical properties • Mapped ATC 5th level drugs to NDF-RT properties • Based on these properties we computed homogeneity scores for all ATC groups and contrasted their distribution against the Micromedex reference • ATC classes are generally homogeneous in terms of clinical properties, especially mechanism of action and physiologic effect, less so for therapeutic use • Incomplete drug description in NDF-RT is a major issue

16. MedicalOntologyResearch Olivier Bodenreider Lister Hill National Centerfor Biomedical CommunicationsBethesda, Maryland - USA Contact: Web: olivier@nlm.nih.gov mor.nlm.nih.gov