SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients

Doki, Kosuke; Homma, Masato; Kuga, Keisuke; Aonuma, Kazutaka; Kohda, Yukinao

doi:10.1097/fpc.0b013e328361fb8d

Cited by 12 publications

(4 citation statements)

References 30 publications

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“…CYP2D6 genotype is a determinant factor of age-related decline in metabolic clearance of flecainide, resulting in a more prominent effect of the CYP2D6 genotype in elderly [51]. Moreover, the therapeutic range of serum concentration is lower in SCN5A promoter haplotype B carriers than in the wild-type haplotype A homozygotes [52]. Concerning drug interactions, CYP2D6 inducers (carbamazepine, phenytoin, phenobarbital, primidone) increase the elimination rate of flecainide [53,54].On the other hand, CYP2D6 inhibitors as amiodarone, protease inhibitors (amprenavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir, tipranavir) [55,56], selective serotonin reuptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline) [57] and serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine) increase flecainide plasma concentration and half-life [58].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Flecainide in Ventricular Arrhythmias: From Old Myths to New Perspectives

Lavalle

Trivigno

Vetta

et al. 2021

JCM

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Flecainide is an IC antiarrhythmic drug (AAD) that received in 1984 Food and Drug Administration approval for the treatment of sustained ventricular tachycardia (VT) and subsequently for rhythm control of atrial fibrillation (AF). Currently, flecainide is mainly employed for sinus rhythm maintenance in AF and the treatment of idiopathic ventricular arrhythmias (IVA) in absence of ischaemic and structural heart disease on the basis of CAST data. Recent studies enrolling patients with different structural heart diseases demonstrated good effectiveness and safety profile of flecainide. The purpose of this review is to assess current evidence for appropriate and safe use of flecainide, 30 years after CAST data, in the light of new diagnostic and therapeutic tools in the field of ischaemic and non-ischaemic heart disease.

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Section: Pharmacokineticsmentioning

confidence: 99%

Flecainide in Ventricular Arrhythmias: From Old Myths to New Perspectives

Lavalle

Trivigno

Vetta

et al. 2021

JCM

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“…However, prospective data to determine its contribution in the face of diminished CYP2D6 expression as noted in this case should be evaluated. In the future, one could also explore gene mutations associated with drug targets as etiologies for flecainide toxicity, namely, SCN5A where selected gene variants have predicted QRS prolongation when challenged with sodium channel blocker (e.g., flecainide) ( 37 , 38 ). The commercial pharmacogenomic platform used in this case report does not have SCN gene mutations included, but should be consider in future expansions of the panel.…”

Section: Discussionmentioning

confidence: 99%

Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia

Palmen,

Sandritter,

Malloy-Walton

et al. 2023

Front. Pediatr.

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Flecainide is a class IC antiarrhythmic utilized in prophylaxis of refractory paroxysmal supraventricular tachycardias in pediatric populations. Despite being a highly effective agent, its narrow therapeutic index increases the risk of toxicity and proarrhythmic events, including wide-complex tachycardia. In the absence of direct plasma sampling in the fetus to quantitate flecainide systemic concentrations, clinicians typically make drug dosing decisions from maternal plasma concentrations and QRS duration on maternal ECGs. There remains a paucity of standard guidelines and data to inform the timing and frequency of the aforementioned test in pregnancy and timing of flecainide discontinuation prior to childbirth. Flecainide primarily undergoes metabolism via cytochrome P450 (CYP). Given the variance of CYP-mediated metabolism at the level of the individual patient, pharmacogenomics can be considered in patients who present with flecainide toxicity to determine the maternal vs. fetal factors as an etiology for the event. Finally, pharmacogenetic testing can be utilized as an adjunct to guide flecainide dosing decisions, but must be done with caution in neonates <2 weeks of age. This case report highlights utilization of pharmacogenomic testing and therapeutic drug monitoring as adjuncts to guide therapy for a newborn with refractory supraventricular tachycardia, who experienced flecainide toxicity immediately post-partum and was trialed unsuccessfully on multiple alternative antiarrhythmics without rhythm control.

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“…Flecainide is a strong sodium channel blocker commonly used to treat various supraventricular tachyarrhythmias. 1,2) Flecainide undergoes hepatic metabolism, and around 40% of a single dose is excreted as an unchanged drug in the urine. 3,4) Since renal impairment prolongs flecainide elimination and thereby increases its serum concentrations, 3) renal excretion of flecainide is a major elimination pathway.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide

Doki

Apáti

Sakata

et al. 2019

Biological & Pharmaceutical Bulletin

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Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide remains unclear except that flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of flecainide, we conducted in vitro interaction studies of flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC 50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2-and hMATE2-K-mediated transport. For investigating flecainide as a substrate of hMATE1, the accumulation of flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 23.9 vs. 11.8 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug-drug interaction for renal excretion of flecainide. However, in vivo drug-drug interaction studies of flecainide with substrates of hMATE1 may be needed because flecainide has the potential to inhibit hMATE1.

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SCN5A promoter haplotype affects the therapeutic range for serum flecainide concentration in Asian patients

Abstract: These findings suggest that the therapeutic range for serum flecainide concentration is lower in HapB carriers than in HapA homozygotes.

Cited by 12 publications

References 30 publications

Flecainide in Ventricular Arrhythmias: From Old Myths to New Perspectives

Flecainide in Ventricular Arrhythmias: From Old Myths to New Perspectives

Case report: Use of therapeutic drug monitoring and pharmacogenetic testing as opportunities to individualize care in a case of flecainide toxicity after fetal supraventricular tachycardia

Involvement of Renal Efflux Transporter MATE1 in Renal Excretion of Flecainide

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