Here are the notes regarding the strong and moderate CYP3A4 substrates used in the data in the accompanying notebook.
drug_name and cyp_strength_of_evidence source
This is all based on the Flockhart table of drug interactions: 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: the enzyme is majorly responsible for drug metabolism.
- Moderate Evidence: the enzyme plays a significant but not exclusive role in drug metabolism or the supporting literature is not extensive.
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.
ADRs data sources
1st-line: Drugs.com
- 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) - likely only available to NZ residents only; other national formularies should contain very similar drug information
electronic medicines compendium (emc) - UK-based drug reference
Drugs@FDA - US-based drug reference
drugs.com_uk_di - UK drug information section in Drugs.com (equivalent to pharmaceutical manufacturers’ medicines information data sheets)
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.)
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
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