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---
title: Notes on adverse drug reactions (ADRs) data
subtitle: For strong and moderate-strengths CYP3A4 substrates
date: '2025-1-8'
date-modified: '2025-2-17'
author: Jennifer HY Lin
draft: false
categories:
- Data
- Notes
jupyter: python3
---
**Update on 15th Feb 2025**: adding ADRs of strong and moderate CYP2D6 substrates slowly from February 2025.
**Additional note re. CYP data on 15th Feb 2025**: **TL;DR: It may be good to add another layer of data complexity (e.g. The Flockhart Cytochrome P450 Drug-Drug Interaction Table) to better reflect real-life drug effects in human uses**. A small discovery re. CYP data used in many ADMET prediction apps - most of them seem to be using *in vitro*-based data (a few other ones use PubChem, which can vary too from different sources e.g. journal papers or from drugbank etc.). I think if the Flockhart table can be added at the same time (to include *in-vivo* evidence in humans, although as I look through some of the citations for drugs in the table, it is also true that not all of them have *in-vivo* human-use evidence, however it should have a decent number of them in it). Overall, this may make ADMET research more well-covered and may improve data quality even more. Another thing is Flockhart table differentiates drugs with strong clinical evidence from the moderate ones, and also other ones pending reviews - this is something *in-vitro* data won't provide.
Here are the notes regarding the strong and moderate CYP3A4 substrates used in the data in the [accompanying notebook](https://jhylin.github.io/Data_in_life_blog/posts/22_Simple_dnn_adrs/2_ADR_regressor.html).
<br>
##### **drug_name and cyp_strength_of_evidence source**
*note: "cyp_strength_of_evidence source" column may be renamed as "cyp_type_and_cyp_strength_of_evidence" when other CYP isoform substrates are added*
This is all based on the Flockhart table of drug interactions: [https://drug-interactions.medicine.iu.edu/MainTable.aspx](https://drug-interactions.medicine.iu.edu/MainTable.aspx)
Strength of evidence that the drug is metabolised by CYP3A4/5 (as quoted from above web link):
- Strong Evidence (may be denoted with s_ followed by CYP name e.g. s_3A4): the enzyme is majorly responsible for drug metabolism.
- Moderate Evidence (may be denoted with m_ followed by CYP name e.g. m_3A4): the enzyme plays a significant but not exclusive role in drug metabolism or the supporting literature is not extensive.
<br>
##### **drug_class data sources**
This information can be found in many national drug formularies, drug reference textbooks e.g. Martindale,
American society of health-System pharmacists' (ASHP) drug information (DI) monographs,
PubChem, ChEMBL, FDA, Micromedex etc. or online drug resources such as Drugs.com. For the particular small dataset collected and used in the notebook, the following reference sources for ADRs also contain information on therapeutic drug classes.
<br>
##### **ADRs data sources**
* 1st-line: [Drugs.com](https://www.drugs.com/sfx/)
- using the health professional version for ADRs which usually contains ADR references from pharmaceutical manufacturers' medicines information data sheets, ASHP DI monographs or journal paper references
* 2nd-line as separate data checks:
- [NZ formulary (nzf)](https://nzf.org.nz/nzf_1) - likely only available to NZ residents only; other national formularies should contain very similar drug information
- [electronic medicines compendium (emc)](https://www.medicines.org.uk/emc) - UK-based drug reference
- [Drugs@FDA](https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm) - US-based drug reference
- [drugs.com_uk_di](https://www.drugs.com/uk/) - UK drug information section in Drugs.com (equivalent to pharmaceutical manufacturers' medicines information data sheets)
- pharmaceutical manufacturers' medicines information data sheets (referenced as "data_sheet") as stated for each drug with notes
- two main types of occurrences/frequencies used:
^^ - common > 10%,
^ - less common 1% to 10%,
(not going to include other ones with lower incidences e.g. less common at 0.1% to 1%, rare for less than 0.1% etc.)
<br>
##### **Exceptions or notes for ADRs**
- nausea and vomiting applies to many drugs so won't be included (almost every drug will have these ADRs, they can be alleviated with electrolytes replacements and anti-nausea meds or other non-med options; rash on the other hand can sometimes be serious and life-threatening e.g. Stevens-Johnson syndrome)
- similar or overlapping adverse effects will be removed to keep only one adverse effect for the same drug e.g. adverse skin reactions, rash, urticaria - rash and urticaria will be removed as allergic skin reactions encompass both symptoms
- for ADR terms with similar meanings, e.g. pyrexia/fever - fever is used instead (only one will be used)
- ADR mentioned in common ADR category and repeated in the less common one will have the ADR recorded in the higher incidence rate (at > 10%) only
- some ADRs can be dose-related or formulations-related e.g. injection site irritations or allergic reactions caused by excipients/fillers (aim is to investigate the relationships between ADRs and drugs via computational tools e.g. any patterns between ADRs & drugs so dose/formulations-related ADRS will not be recorded here)
- some postmarketing adverse effects are for different age populations e.g. paediatric patients of up to 12 years of age or elderly people - for now all of them are labelled as "(pm)" to denote postmarketing reports and are not differentiated in age groups
###### **Notes for specific drugs**
- hydrocortisone (a moderate CYP3A4 substrate) has no reported ADR frequencies at all for its ADRs as they are entirely dependent on the dosage and duration of use (ADRs tend to be unnoticeable at appropriate low doses for short durations)
- terfenadine (a strong CYP3A4 substrate) is actually withdrawn from the market in 1990s due to QT prolongations
- lercanidipine (a moderate CYP3A4 substrate) has nil reported ADRs of more than 1% but has a few postmarketing reports recorded
- telaprevir (a moderate CYP3A4 substrate) is usually administered within a combination therapy (e.g. along with peginterferon alfa and ribavirin)
- quinine (a moderate CYP3A4 substrate) has all of its ADRs reported without frequencies. The most common ADRs are presented as a cluster of symptoms (known as cinchonism) and can occur during overdoses (usually very toxic) and also normal doses. These symptoms include "...tinnitus, hearing impairment, headache, nausea, vomiting, abdominal pain, diarrhoea, visual disturbances (including blindness), arrhythmias (which can have a very rapid onset), convulsions (which can be intractable), and rashes." (as quoted from NZ formulary v150 - 01 Dec 2024)
- ribociclib (a moderate CYP3A4 substrate) has a listed ADR of on-treatment deaths, which were found to be associated with patients also taking letrozole or fulvestrant at the same time and/or in patients with underlying malignancy
- nortriptyline (a strong CYP2D6 substrate) has no frequencies recorded for all of its ADRs - the recorded ADRs in files will be mainly based on nzf which has stated these ADRs as common ones with varying risk and extent, a good rule of thumb is to be aware of the well-known tricyclic antidepressant-related ADRs e.g. antimuscarinic effects (dry mouth, blurred vision, constipation, urinary retention)
- perhexiline (a strong CYP2D6 substrate) has no records of medicines information in Drugs@FDA or Drugs.com so the main source of drug information is nzf and its pharmaceutical manufacturer's [medicines data sheet](https://www.medsafe.govt.nz/profs/datasheet/p/pexsigtab.pdf). The ADRs may be present for the first two to four weeks of treatment only
<br>
##### **Abbreviations used**
- ws = withdrawal symptoms
- ADH = antidiuretic hormone
- pm = postmarketing reports
- CNS = central nervous system
- CFTR = cystic fibrosis transmembrane regulator
- c_diff = Clostridioides/Clostridium difficile
- ZE = Zollinger-Ellison
- MTOR = mammalian target of rapamycin (protein kinase)
- AST = aspartate transaminase/aminotransferase
- ALT = alanine transaminase/aminotransferase
- ALP = alkaline phosphatase
- GGT = gamma-glutamyltransferase
- RTI = respiratory tract infection
- UTI = urinary tract infection
- LDH = lactate dehydrogenase
- dd = dose and duration-dependent
- pm_HIV_pit = postmarketing reports for HIV protease inhibitor therapy
- pm_hep_cyto = postmarketing reports in cancer patients where drug was taken with hepatotoxic/cytotoxic chemotherapy and antibiotics
- BUN = blood urea nitrogen