Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.

PURPOSE: Higher drug concentrations in complex clinical scenarios in which multiple factors such as drug-drug interactions (DDIs) and comorbidities are simultaneously present are not necessarily rationalized in prospective clinical studies. Physiologically based pharmacokinetic (PBPK) modeling and simulation of the anti-arrhythmic drug flecainide, as an example, were utilized to quantitatively rationalize the higher flecainide concentration in a complex clinical case involving end-stage renal disease (ESRD), cirrhosis, and the co-administration of mexiletine, a CYP1A2 inhibitor. METHODS: The developed flecainide PBPK model was used to evaluate the DDI effect (as measured by AUC ratio before and after inhibition) of mexiletine and the combined disease effects of ESRD and cirrhosis on flecainide exposure. RESULTS: The predicted DDI effect of mexiletine was negligible or weak in anuric hemodialysis with cirrhosis population (mean [5th/95th percentiles], 1.23 [0.97-1.67]), although it was negligible in healthy volunteers (1.03 [1.02-1.05]). The predicted flecainide concentrations after multiple flecainide doses (50 mg BID) in the anuric hemodialysis with cirrhosis population were comparable with the observed value (3602 ng/mL), which fell between the predicted concentrations in the absence and presence of mexiletine (3043 [718-8499] and 5914 [880-20,624] ng/mL, respectively). CONCLUSIONS: The PBPK simulation proposed a likely explanation that the observed higher flecainide concentration could be attributed to the combined effects of ESRD, cirrhosis, and a potential DDI with mexiletine. This approach provides quantitative insight into theoretically conceivable extremes in drug exposure occurring in complex clinical situations even if uncommon.

Pulmonary Delivery of Antiarrhythmic Drugs for Rapid Conversion of New-Onset Atrial Fibrillation.

Pharmacologic management of atrial fibrillation (AF) is a pressing problem. This arrhythmia afflicts >5 million individuals in the United States and prevalence is estimated to rise to 12 million by 2050. Although the pill-in-the-pocket regimen for self-administered AF cardioversion introduced over a decade ago has proven useful, significant drawbacks exist. Among these are the relatively long latency of effects in the range of hours along with potential for hypotension and other adverse effects. This experience prompted development of a new strategy for increasing plasma concentrations of antiarrhythmic drugs rapidly and for a limited time, namely, pulmonary delivery. In preclinical studies in Yorkshire pigs, intratracheal administration of flecainide was shown to cause a rapid, reproducible increase in plasma drug levels. Moreover, pulmonary delivery of flecainide converted AF to normal sinus rhythm by prolonging atrial depolarization, which slows intra-atrial conduction and seems to be directly correlated with efficacy in converting AF. The rapid rise in plasma flecainide levels optimizes its anti-AF effects while minimizing adverse influences on ventricular depolarization and contractility. A more concentrated and soluble formulation of flecainide using a novel cyclodextrin complex excipient reduced net drug delivery for AF conversion when compared to the acetate formulation. Inhalation of the beta-adrenergic blocking agent metoprolol slows ventricular rate and can also terminate AF. In human subjects, oral inhalation of flecainide acetate with a hand-held, breath-actuated nebulizer results in signature prolongation of the QRS complex without serious adverse events. Thus, pulmonary delivery is a promising advance in pharmacologic approach to management of AF.

Renal failure, shock, and loss of pacemaker capture: A case of flecainide intoxication.

Flecainide intoxication is a severe intoxication that can lead to cardiogenic shock. We report on a 68-year-old female patient, who presented with a flecainide intoxication in the setting of renal failure. She was managed with invasive supportive therapy at the ICU and infusion of sodium bicarbonate and intravenous lipid emulsion (ILE, intralipid 20%), after which she made a complete recovery.

Optimizing flecainide plasma concentration profile for atrial fibrillation conversion while minimizing adverse ventricular effects by rapid, low-dose intratracheal or intravenous administration.

BACKGROUND: We investigated whether rapid administration of a low dose of flecainide, either intratracheally or intravenously (IV), could accelerate conversion of atrial fibrillation (AF) while reducing adverse ventricular effects. METHODS: Flecainide was delivered via intratracheal administration at 1.5 mg/kg bolus and compared to IV infusion at 1.0 mg/kg over 2 min (lower-dose, rapid) and 2.0 mg/kg over 10 min (ESC guideline) in closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in right atrium to measure atrial depolarization (Pa) duration and left ventricle (LV) to measure QRS complex duration and contractility (LV dP/dt) during atrial pacing at 140 beats/min. Flecainide was delivered intratracheally via a catheter positioned at the bifurcation of the main bronchi. AF was induced by intrapericardial administration of acetylcholine followed by burst pacing. RESULTS: Flecainide reduced AF duration similarly by intratracheal and IV delivery. Peak plasma levels were comparable but Tmax differed and coincided with peaks in Pa prolongation. The area under the curve indicating sustained plasma levels was greater for higher-dose, slow IV flecainide than for either intratracheal instillation (by 32%) or lower-dose, rapid IV infusion (by 88%). As a result, higher-dose, slow IV flecainide caused 58% (p < 0.03) and 48% (p < 0.006) greater increases in QRS complex duration and 61% and 96% (both, p < 0.02) greater reductions in contractility compared to intratracheal and lower-dose, rapid IV flecainide, respectively. CONCLUSION: Lower-dose, rapid flecainide, delivered either intratracheally or IV, optimizes the plasma concentration profile for effective conversion of AF while minimizing adverse effects on QRS complex duration and LV contractility.

[Use of Pharmacogenetic Information for Therapeutic Drug Monitoring of an Antiarrhythmic Drug].

　Antiarrhythmic drugs require therapeutic drug monitoring (TDM) to avoid adverse effects such as proarrhythmia. However, TDM is not necessarily used to adjust the dosage of antiarrhythmic drugs because there is a lack of information regarding the therapeutic range of the serum concentration and the selection of patients who require TDM. The aim of this review was to provide an overview of the pharmacogenetic information on the pharmacokinetics and drug response of flecainide, a class Ic antiarrhythmic drug with a sodium channel-blocking effect. A population pharmacokinetic analysis revealed that the CYP2D6 genotype was a determining factor of the age-related decline in flecainide clearance. Elderly patients show large interindividual variability of flecainide clearance because they have a more pronounced effect of the CYP2D6 genotype and require more frequent monitoring of serum flecainide concentrations. Carriers of an Asian-specific promoter haplotype B of the cardiac sodium channel gene (SCN5A) more frequently achieve clinically relevant flecainide efficacy even at lower concentrations. This suggests that the therapeutic range of serum flecainide concentrations is lower in SCN5A promoter haplotype B carriers than in the wild-type haplotype A homozygotes. The ß1-adrenergic receptor Gly389 polymorphism decreases the antiarrhythmic efficacy of flecainide when co-administered with ß-blockers. Carriers of Gly389 with co-administration of ß-blockers may not achieve clinically relevant flecainide efficacy even when the serum flecainide concentrations are within the therapeutic range. These findings provide pharmacogenetic information for the effective utilization of TDM in antiarrhythmic drug therapy.

Comparative Pharmacokinetic and Electrocardiographic Effects of Intratracheal and Intravenous Administration of Flecainide in Anesthetized Pigs.

We compared the pharmacokinetic (PK) profile and electrocardiographic (ECG) changes in response to intratracheal instillation of flecainide acetate into the left atrium and ventricle with intravenous (IV) flecainide acetate administration. In 12 closed-chest anesthetized Yorkshire pigs, we monitored the QRS complex and PR, JTc, and QTc intervals during sinus rhythm and correlated changes with venous plasma drug concentrations before and at 2, 5, 10, 15, and 30 minutes after drug administration. Intratracheal instillation of flecainide (0.75 and 1.5 mg/kg, rapid bolus) caused dose/concentration-dependent increases in the QRS complex duration of 10% and 19%, respectively, at 2 minutes, coinciding with peak venous plasma levels (1688 ± 177 and 2808 ± 217 ng/mL, respectively). IV infusion of flecainide (2 mg/kg) over 2 or 10 minutes similarly prolonged QRS complexes and PR intervals (both, P < 0.001). Intratracheal flecainide instillation increased PR interval briefly at 5 minutes. Neither intratracheal nor IV flecainide affected JTc or QTc intervals. Thus, the PK pattern of intratracheal instillation of flecainide is comparable to IV administration, although the absolute plasma concentrations were higher with IV infusion. Both modes of delivery elicited ECG changes that were consistent with the expected pharmacological activity of flecainide.

Lesson of the month 1: Acute flecainide overdose and the potential utility of lipid emulsion therapy.

Lipid-emulsion therapy (Intralipid®) has been advocated as a potential treatment for the management of cardio-toxicity arising from lipid-soluble drugs, particularly those acting upon sodium channels. This, on the basis of a number of ex vivo studies and animal models, suggests that partitioning a drug into lipid could alter its pharmacokinetics and result in significant clinical improvements. Its subsequent use in clinical case series has been seen as confirmation of this mechanism of action. While there are undoubtedly instances where lipid emulsion therapy has been associated with a desirable outcome in humans, as described in this case report, clinicians are reminded that they should not attribute causality, on this basis alone.

Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide.

PURPOSE: The therapeutic index (TI) is the range of doses at which a medication is effective without unacceptable adverse events. Drugs with a narrow TI (NTIDs) have a narrow window between their effective doses and those at which they produce adverse toxic effects. Generic drugs may be substituted for brand-name drugs provided that they meet the recommended bioequivalence (BE) limits. However, an appropriate range of BE for NTIDs is essential to define due to the potential for ineffectiveness or adverse events. Flecainide is an antiarrhythmic agent that has the potential to be considered an NTID. This review aims to evaluate the literature surrounding guidelines on generic substitution for NTIDs and to evaluate the evidence for flecainide to be considered an NTID. METHODS: A review of recommendations from various regulatory authorities regarding BE and NTIDs, and publications regarding the NTID characteristics of flecainide, was carried out. RESULTS: Regulatory authorities generally recommend reduced BE limits for NTIDs. Some, but not all, regulatory authorities specify flecainide as an NTID. The literature review demonstrated that flecainide displays NTID characteristics including a steep drug dose-response relationship for safety and efficacy, a need for therapeutic drug monitoring of pharmacokinetic (PK) or pharmacodynamics measures and intra-subject variability in its PK properties. CONCLUSIONS: There is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide.

Correlation of maternal flecainide concentrations and therapeutic effect in fetal supraventricular tachycardia.

BACKGROUND: Transplacental flecainide is an established therapy for fetal supraventricular tachycardia (SVT), but there is a paucity of data regarding the dose-response relationship. OBJECTIVE: The purpose of this study was to investigate the relationship between maternal flecainide concentrations, arrhythmia control, and adverse fetal effects in fetal SVT. METHODS: Fetuses with SVT treated with transplacental flecainide at our tertiary fetal cardiology unit between 1997 and 2012 were retrospectively studied. The maternal trough flecainide concentrations throughout treatment were collated, and clinical notes were reviewed to ascertain the response to therapy and fetal outcome. RESULTS: Thirty-three fetuses were treated at a median (range) gestation of 28 weeks (20-38 weeks). Median fetal heart rate was 250/min (range 207-316/min). One patient was lost to follow-up, and this fetus was excluded from further analysis. In total, 25 of 32 fetuses (78%) converted to sinus rhythm. Median time to conversion to sinus rhythm was 3 days (range 2-12 days). Median flecainide concentration was 460 µg/L (range 250-866 µg/L) at conversion to sinus rhythm. Flecainide concentrations were not significantly different between responders and nonresponders (P = .849). Twelve of 14 hydropic and 13 of 18 nonhydropic fetuses converted to sinus rhythm with similar flecainide concentrations (P = .316). No fetus achieved cardioversion with a maternal serum flecainide concentration <250 µg/L. No fetus died while being treated with flecainide. CONCLUSION: The clinical response to flecainide appears good, even in hydropic fetuses. Trough maternal flecainide concentrations, once therapeutic, do not predict cardioversion in the fetus with SVT. Flecainide therapy appears both safe and effective for the fetus when monitored appropriately.

Pharmacokinetic variability of flecainide in younger Japanese patients and mechanisms for renal excretion and intestinal absorption.

The aims of the present study were to evaluate the variability of pharmacokinetics of flecainide in young Japanese patients and to investigate the mechanisms of renal excretion and intestinal absorption of the drug using cultured epithelial cells. First the plasma concentration data of flecainide was analysed in 16 Japanese patients aged between 0.07 and 18.30 years using a one-compartment model. Considerable interindividual variability was observed in the oral clearance (CL/F) and the apparent volume of distribution (V/F) of flecainide in the young patients. Flecainide was transported selectively in the basolateral-to-apical direction in P-glycoprotein-expressing renal epithelial LLC-GA5-COL150 cell monolayers. The uptake of flecainide into intestinal epithelial LS180 cells was decreased significantly by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine. These findings in the present study suggest that flecainide is excreted by P-glycoprotein in the renal tubule and is taken up by the postulated H(+)/tertiary amine antiporter in the intestine, and that functional variability of not only the hepatic drug-metabolizing enzymes, but also the transporters in the kidney and intestine, may be responsible for the interindividual variability of systemic clearance (CL) and/or the bioavailability (F) of flecainide.

Pharmacokinetic-pharmacodynamic modeling of QRS-prolongation by flecainide: heart rate-dependent effects during sinus rhythm in conscious telemetered dogs.

INTRODUCTION: The duration of the QRS interval is determined by the ion currents involved in cardiac depolarization. Class I antiarrhythmic drugs reduce cardiac excitability and conduction by inhibiting Nav1.5 channels responsible for I(Na), thus increasing the QRS interval. Previous studies in humans as well as in animal models have demonstrated a more pronounced effect on QRS-prolongation during higher heart rates. In the present study, the effects of the Nav1.5 inhibitor flecainide on cardiovascular parameters, were studied in the telemetered beagle dog under normal autonomic control. The heart rate dependency of QRS prolongation was characterized using pharmacokinetic-pharmacodynamic (PKPD) modeling. METHODS: Four male telemetered beagle dogs were administered placebo or flecainide (100, 150 and 200 mg) in a Latin square design. The QRS interval and heart rate were recorded, and blood samples were taken. Plasma concentrations of flecainide were fitted to a one compartment oral model and the intrapolated plasma concentrations were fitted to QRS and heart rate data sampled during 5 h after dosing. RESULTS: Flecainide increased the QRS interval in all dogs, whereas there were no effects on heart rate. Using the PKPD model, a statistically significant heart rate-dependent QRS prolongation was linked to individual concentration-time profiles of flecainide. DISCUSSION: PKPD analysis of QRS interval data from unrestrained dogs with sinus rhythm can elucidate mechanisms previously only described during controlled heart rhythm. Specific questions can therefore be addressed in generically designed cardiovascular telemetry safety studies and different types of relationships between parameters can be uncovered. In addition, the present approach can be used to better characterize drug-induced QRS effects in cardiovascular dog models.

CYP2D6 genotype affects age-related decline in flecainide clearance: a population pharmacokinetic analysis.

OBJECTIVE: To investigate the association between age-related decline in flecainide clearance and CYP2D6 genotype, we conducted a population pharmacokinetic analysis of flecainide using routine therapeutic drug monitoring data. METHODS: Population pharmacokinetic analysis was performed on retrospective data from 163 genotyped patients treated with oral flecainide for supraventricular tachyarrhythmias. The CYP2D6 genotype was categorized as CYP2D6 homozygous extensive metabolizers (hom-EMs; n=57), heterozygous extensive metabolizers (het-EMs; n=79), and intermediate metabolizers and poor metabolizers (IMs/PMs; n=27). RESULTS: Population pharmacokinetic analysis revealed that estimated glomerular filtration rate, body weight, female sex, and aging were important factors for estimating flecainide clearance. The metabolic clearance was decreased age dependently in a curvilinear fashion, where the lower clearance was observed in greater than 60 years for het-EMs and greater than 55 years for IMs/PMs. The reduction in metabolic clearance in elderly (70 years) patients compared with middle-aged (52 years) patients was different among the CYP2D6 genotype groups: 22.1 and 49.5% in CYP2D6 het-EMs and IMs/PMs, respectively, and no change in hom-EMs. A 11.4% reduction in estimated glomerular filtration rate in elderly patients compared with middle-aged patients corresponded to 6.1% decline in flecainide clearance. Overall, the age-related decline in flecainide clearance was 6.1% in hom-EMs, 16.3% in het-EMs, and 28.9% in IMs/PMs groups. CONCLUSION: This study suggests that CYP2D6 genotype is a determinant factor of age-related decline in flecainide clearance.

Flecainide and antiarrhythmic effects in a mouse model of catecholaminergic polymorphic ventricular tachycardia.

Recent studies have shown that flecainide may be an effective therapy to prevent life-threatening arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Several hypotheses have been advanced to explain the antiarrhythmic mechanism of flecainide, including Na(+) channel blockade and a direct inhibitory action on the ryanodine receptor. In this article, we review the current literature on the topic and summarize the elements of the existing debate.

Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects.

BACKGROUND: Although flecainide is thought to be meta-bolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics. METHODS: Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms. RESULTS: There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0-∞) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p<0.05). Subjects homozygous for CYP1A2*1F tended to have lower systemic exposure and increased clearance of flecainide compared to those with CYP1A2*1A/1F in subjects with at least one CYP2D6 variant allele. CONCLUSIONS: The disposition of flecainide appeared to be influenced by the CYP3A5*3 and possibly the CYP1A2*1F polymorphisms, particularly in subjects with CYP2D6 variant alleles.

Safety of flecainide.

Flecainide is a class Ic antiarrhythmic agent that has an important role as part of rhythm control strategies in patients with atrial fibrillation (AF). Early clinical data on the use of flecainide showed an increase in arrhythmias and mortality compared with placebo in patients with a previous myocardial infarction and asymptomatic or mildly symptomatic ventricular arrhythmias. These findings only apply to a specific group of patients with left ventricular dysfunction and ischaemic heart disease, but had a negative impact on the use of class Ic antiarrhythmics across all indications and patient groups. The aim of this review was to evaluate the available safety data for flecainide in the literature and to assess its current use in patients with AF. Current European guidelines now recommend the use of flecainide in carefully selected groups of patients with AF who do not have structural heart disease. This includes for the cardioversion of recent-onset AF, pretreatment prior to direct current cardioversion, out-of-hospital acute oral therapy ('pill-in-the-pocket' approach) and for the ongoing maintenance of sinus rhythm. Potential cardiac adverse effects of flecainide include proarrhythmia, conduction abnormalities and negative inotropic effects. Dizziness is the most frequent non-cardiac side effect, followed by blurred vision and difficulty focusing; these are almost all mild, transient and tolerable. Data from recent clinical trials in patients with supraventricular arrhythmias suggest that flecainide has a good tolerability profile in groups of appropriately selected patients. Caution is required when using flecainide in patients with renal dysfunction, and there are a number of drug interactions, but these are well documented and manageable. Overall, flecainide is a good choice for the pharmacological management of AF. It has a good safety record and low incidence of adverse effects, rare end-organ toxicity and a low risk of ventricular proarrhythmia. To ensure that the benefits of treatment outweigh any potential risks, careful patient selection and monitoring is required.

Usefulness of postmortem biochemistry in forensic pathology: illustrative case reports.

The aim of this work is to present some practical, postmortem biochemistry applications to illustrate the usefulness of this discipline and reassert the importance of carrying out biochemical investigations as an integral part of the autopsy process. Five case reports are presented pertaining to diabetic ketoacidosis in an adult who was not known to suffer from diabetes and in presence of multiple psychotropic substances; fatal flecainide intoxication in a poor metabolizer also presenting an impaired renal function; diabetic ketoacidosis showing severe postmortem changes; primary aldosteronism presented with intracranial hemorrhage and hypothermia showing severe postmortem changes. The cases herein presented can be considered representative examples of the importance of postmortem biochemistry investigations, which may provide significant information useful in determining the cause of death in routine forensic casework or contribute to understanding the pathophysiological mechanisms involved in the death process.

Comparison of the in vivo hemodynamic effects of the antiarrhythmic agents vernakalant and flecainide in a rat hindlimb perfusion model.

A series of in vivo experiments were conducted to compare the hemodynamic actions of vernakalant (a novel, relatively atrial selective, antiarrhythmic drug) to flecainide after infusion into the peripheral vasculature. Anesthetized rats were surgically prepared to have an extracorporeal perfusion circuit whereby blood in the abdominal aorta (distal to the renal arteries) was diverted to a constant flow pump and returned to the abdominal aorta at the same level allowing measurement of hindlimb vascular resistance. The effects of cumulative, ascending doses of intravenous vernakalant and flecainide on vascular resistance, after arterial pressures, and heart rate were measured. Blood samples were drawn following each dose to determine drug plasma concentrations. Vernakalant had no significant vasomotor effects on peripheral or systemic vasculature. In contrast, flecainide decreased peripheral vascular resistance (15% at 0.8 µg/mL) and systemic pressures (32% mean arterial pressure at 0.8 µg/mL) in a dose-dependent manner. At therapeutic plasma concentrations, vernakalant (1 µg/mL) had little effect on heart rate (-24 beats/min) or QRS intervals (+3.4 msec), whereas flecainide (0.8 µg/mL) significantly decreased heart rate (55 beats/min) and increased QRS intervals (9.9 msec). In conclusion, vernakalant did not have negative hemodynamic effects at therapeutic plasma concentrations in a rat hindlimb perfusion model.

[Flecainide poisoning]. / Intoxicación por flecainida.

Flecainide is an antiarrhythmic drug that blocks sodium channels during phase 0 of cardiac action potential, delaying conduction and reducing contractility. Intoxication by this drug is rare. Onset of effect, which is rapid, takes the form of hypotension and cardiac arrhythmias; mortality is high. No antidote is available and management is based on the few cases that have been reported. The metabolism of flecainide is affected by both kidney and liver failure, which lead to accumulation of the drug. Flecainide should not be used in patients with such failure unless the potential benefits clearly outweigh the risks. If flecainide is prescribed, diligent clinical, electrocardiographic, and hemodynamic vigilance is imperative and plasma levels of the drug should be monitored. We report a case of flecainide poisoning in which the drug was prescribed to treat atrial fibrillation in a woman with resolving sepsis with renal and hepatic complications.