Influence of <i>CYP2D6</i> genetic variation on adverse events with propafenone in the pediatric and young adult population

Sunthankar, Sudeep; Kannankeril, Prince J.; Gaedigk, Andrea; Radbill, Andrew E.; Fish, Frank A.; Driest, Sara L. Van

doi:10.1111/cts.13296

Cited by 4 publications

(1 citation statement)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Zhender et al [8] observed nausea and vomiting at short-term higher therapeutic doses and the exacerbation of ventricular extrasystoles during long-term treatment. Various studies also describe a proarrhythmic adverse effect, such as wide complex tachycardia or QRS broadening [9]; electrocardiogram-associated adverse events (prolonged QRS and QTc, first-and second-degree atrioventricular nodal block, bradycardia); and systematic adverse events (hypotension, dizziness, dysgeusia, fatigue, irritation and gastrointestinal intolerance) [10]. The coadministration of metoprolol and verapamil also increases the risk of toxicity [11,12].…”

Section: Introductionmentioning

confidence: 99%

A Tissue Distribution Study of Propafenone in an Intentional Fatal Poisoning Case

Nižnanská,

Hengerics Szabó,

Masár

et al. 2024

IJMS

View full text Add to dashboard Cite

Propafenone (PPF) belongs to the class 1C antiarrhythmics and can cause electrocardiogram-associated adverse/toxic effects. Cases of PPF intoxication are rarely investigated. We developed a novel and selective GC-MS/MS method for the determination of PPF and its tissue distribution in an intentional fatal poisoning case, which is applicable to PPF quantification in the range of therapeutic to lethal concentrations in complex post-mortem samples. A simple and effective sample pretreatment was applied to all analyzed samples. PPF was determined without the need for dilution, even in highly complex samples containing a wide range of analyte concentrations. Quantification was performed using the standard addition method, developed and validated according to the ICH M10 guidelines. The obtained results indicated that the PPF concentration in the serum from blood taken while alive, before therapy, was the highest ever reported in the literature. Despite the intensive therapy after the patients’ admission, the PPF concentrations in the lungs, spleen, femoral blood and cardiac blood were fatal or abnormally high. On the other hand, the concentrations in the liver and skeletal muscle were lower or approximately the same as observed in cases with therapeutic doses. To the best of our knowledge, the distribution of PPF has not been investigated in fatal intoxication cases and can be helpful in clinical or forensic toxicology.

show abstract

Section: Introductionmentioning

confidence: 99%

A Tissue Distribution Study of Propafenone in an Intentional Fatal Poisoning Case

Nižnanská,

Hengerics Szabó,

Masár

et al. 2024

IJMS

View full text Add to dashboard Cite

show abstract

Discovering Severe Adverse Reactions From Pharmacokinetic Drug–Drug Interactions Through Literature Analysis and Electronic Health Record Verification

Jeong,

Su,

et al. 2024

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

While drug–drug interactions (DDIs) and their pharmacokinetic (PK) mechanisms are well‐studied prior to drug approval, severe adverse drug reactions (SADRs) caused by DDIs often remain underrecognized due to limitations in pre‐marketing clinical trials. To address this gap, our study utilized a literature database, applied natural language processing (NLP) techniques, and conducted multi‐source electronic health record (EHR) validation to uncover underrecognized DDI‐SADR signals that warrant further investigation. PubMed abstracts related to DDIs from January 1962 to December 2023 were retrieved. We utilized PubTator Central for Named Entity Recognition (NER) to identify drugs and SADRs and employed SciFive for Relation Extraction (RE) to extract DDI‐SADR signals. The extracted signals were cross‐referenced with the DrugBank database and validated using logistic regression, considering risk factors including patient demographics, drug usage, and comorbidities, based on EHRs from Vanderbilt University Medical Center (VUMC) and the All of Us research program. From 160,321 abstracts, we identified 111 DDI‐SADR signals. Seventeen were statistically significant (13 by one EHR and 4 by both EHR databases), with 9 being previously not recorded in the DrugBank. These included methadone‐ciprofloxacin‐respiratory depression, oxycodone‐fluvoxamine‐clonus, tramadol‐fluconazole‐hallucination, simvastatin‐fluconazole‐rhabdomyolysis, ibrutinib‐amiodarone‐atrial fibrillation, fentanyl‐diltiazem‐delirium, clarithromycin‐voriconazole‐acute kidney injury, colchicine‐cyclosporine‐rhabdomyolysis, and methadone‐voriconazole‐arrhythmia (odds ratios (ORs) ranged from 1.9 to 35.83, with P‐values ranging from < 0.001 to 0.017). Utilizing NLP to extract DDI‐SADRs from Biomedical Literature and validating these findings through multiple‐source EHRs represents a pioneering approach in pharmacovigilance. This method uncovers clinically relevant SADRs resulting from DDIs that were not evident in pre‐marketing trials or the existing DDI knowledge base.

show abstract

Influence of CYP2D6 genetic variation on adverse events with propafenone in the pediatric and young adult population

Sunthankar

Kannankeril

Gaedigk

et al. 2022

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

Propafenone is an antiarrhythmic drug metabolized primarily by cytochrome P450 2D6 (CYP2D6). In adults, propafenone adverse events (AEs) are associated with CYP2D6 poor metabolizer status; however, pediatric data are lacking. Subjects were tested for 10 CYP2D6 allelic variants and copy number status, and activity scores assigned to each genotype. Seventy‐six individuals (median 0.3 [range 0–26] years old) were included. Propafenone AEs occurred in 29 (38%); 14 (18%) required drug discontinuation due to AE. The most common AEs were QRS (n = 10) and QTc (n = 6) prolongation. Those with AEs were older at the time of propafenone initiation (1.58 [0.13–9.92] vs. 0.20 [0.08–2.01] years old; p = 0.042). CYP2D6 activity scores were not associated with presence of an AE (odds ratio [OR] 0.48 [0.22–1.03]; p = 0.055) but with the total number of AE (β1 = −0.31 [−0.60, −0.03]; p = 0.029), systemic AEs (OR 0.33 [0.13–0.88]; p = 0.022), and drug discontinuation for systemic AEs (OR 0.28 [0.09–0.83]; p = 0.017). Awareness of CYP2D6 activity score and patient age may aid in determining an individual's risk for an AE with propafenone administration.

show abstract

Influence of CYP2D6 genetic variation on adverse events with propafenone in the pediatric and young adult population

Cited by 4 publications

References 32 publications

A Tissue Distribution Study of Propafenone in an Intentional Fatal Poisoning Case

A Tissue Distribution Study of Propafenone in an Intentional Fatal Poisoning Case

Discovering Severe Adverse Reactions From Pharmacokinetic Drug–Drug Interactions Through Literature Analysis and Electronic Health Record Verification

Influence of CYP2D6 genetic variation on adverse events with propafenone in the pediatric and young adult population

Contact Info

Product

Resources

About