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

Abstract

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.

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

“…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].…”