Plasma Amiodarone Research Articles

Evaluation of the pharmacokinetics and bioavailability of intravenously and orally administered amiodarone in horses

To determine the clinical effects and pharmacokinetics of amiodarone after single doses of 5 mg/kg administered orally or intravenously. 6 healthy adult horses. In a cross over study, clinical signs and electrocardiographic variables were monitored and plasma and urine samples were collected. A liquid chromatography-mass spectrometry method was used to determine the percentage of protein binding and to measure plasma and urine concentrations of amiodarone and the active metabolite desethylamiodarone. No adverse clinical signs were observed. After IV administration, median terminal elimination half-lives of amiodarone and desethylamiodarone were 51.1 and 75.3 hours, respectively. Clearance was 0.35 L/kg x h, and the apparent volume of distribution for amiodarone was 31.1 L/kg. The peak plasma desethylamiodarone concentration of 0.08 microg/mL was attained 2.7 hours after IV administration. Neither parent drug nor metabolite was detected in urine, and protein binding of amiodarone was 96%. After oral administration of amiodarone, absorption of amiodarone was slow and variable; bioavailability ranged from 6.0% to 33.7%. The peak plasma amiodarone concentration of 0.14 microg/mL was attained 7.0 hours after oral administration and the peak plasma desethylamiodarone concentration of 0.03 microg/mL was attained 8.0 hours after administration. Median elimination half-lives of amiodarone and desethylamiodarone were 24.1 and 58.6 hours, respectively. Results indicate that the pharmacokinetic distribution of amiodarone is multicompartmental. This information is useful for determining treatment regimens for horses with arrythmias. Amiodarone has low bioavailability after oral administration, does not undergo renal excretion, and is highly protein-bound in horses.

Pharmacokinetics of Amiodarone in hyperlipidemic and simulated high fat‐meal rat models

The objective of this study was to examine the effect of a high fat meal and hyperlipidemia on the pharmacokinetic behavior of amiodarone. To evaluate these effects, single doses of amiodarone were administered to rats i.v. (25 mg/kg) or orally (50 mg/kg). Some rats were rendered hyperlipidemic by intraperitoneal doses of poloxamer 407 followed by amiodarone i.v. In other normolipidemic rats, amiodarone was administered i.v. in a fasted state or after the administration of 1% cholesterol in peanut oil. Amiodarone plasma concentrations were considerably (>11-fold) increased in hyperlipidemia. Substantial decreases were noted in the clearance, volume of distribution and unbound fraction (11.6, 23 and 24.7-fold, respectively) in plasma of hyperlipidemic rats. Oral lipid caused a significant increase in plasma AUC(0-infinity) (1.38-fold) and a significant decrease in clearance (1.5-fold) of amiodarone after intravenous doses. Oral consumption of 1% cholesterol in peanut oil significantly increased the plasma AUC (1.83-fold) and bioavailability of amiodarone (1.31-fold) after oral doses. In determining oral bioavailability of lipophilic drugs such as amiodarone in food effect studies, in addition to the increase in absorption of drugs, other factors such as a decrease in clearance due to increases in lipoprotein levels should be taken into account.

Phenylacetylglycine, a putative biomarker of phospholipidosis: Its origins and relevance to phospholipid accumulation using amiodarone treated rats as a model

Amiodarone was given to male Sprague–Dawley rats at a dose of 150 mg kg−1 day−1 for 7 consecutive days to induce phospholipidosis in the lungs of treated rats. Amiodarone was given alone or concurrently with phenobarbitone. Animals given amiodarone had raised total phospholipid in serum, lung and lymphocytes, and elevated lyso(bis)phosphatidic acid (LBPA) in all tissues. Urinary and plasma phenylacetylglycine (PAG) and hepatic portal:aortal phenylacetate (PA) ratio were increased, whereas hepatic phenylalanine hydroxylase (PAH) activity and plasma phenylalanine:tyrosine ratio were not affected. Phenobarbitone treatment increased hepatic total P450 content and induced 7-pentoxyres-orufin O-dealkylatian (PROD) activity, as expected, but had no effect on any other biochemical parameter. Plasma amiodarone concentration was reduced in rats co-administered both drugs and phospholipid accumulation in target tissues was attenuated compared with rats treated with amiodarone alone. However, phenobarbitone co-administration failed to alter the magnitude of response with regards to urinary PAG excretion and plasma concentration of its precursors after amiodarone treatment. Increased intestinal absorption of PAG precursors probably resulted in the raised urinary PAG after amiodarone treatment. Urinary PAG correlated weakly with serum, lymphocyte and lung phospholipids. However, urinary PAG excretion was similar in rats dosed solely with amiodarone or in combination with phenobarbitone, despite the fact that the degree of phospholipid accumulation was far less in rats given the combined treatment. Nevertheless, urinary PAG was raised only in animals exhibiting abnormal phospholipid accumulation in target tissues and may thus be useful as a surrogate biomarker for phospholipidosis.

Myocardial amiodarone concentrations after short- and long-term treatment in patients with end-stage heart failure.

Pharmacokinetics and tissue concentrations of amiodarone may vary considerably in end-stage heart failure, but may be crucial for treatment efficiency and antiarrhythmic drug therapy. This study was undertaken to determine plasma amiodarone and desethylamiodarone concentrations and to determine whether they correlate with myocardial concentrations in explanted hearts from patients with end-stage heart failure. Eight patients with idiopathic dilated cardiomyopathy and normal coronary arteries were included in the present study. Myocardial tissue samples (seven sites) and epicardial fat were taken from each explanted heart, and drug concentrations of amiodarone and desethylamiodarone were determined. In addition, plasma drug levels were measured and compared with the myocardial amiodarone/desethylamiodarone concentrations. The mean cumulative amiodarone dose was 91 g and the mean plasma concentrations of amiodarone and desethylamiodarone were 0.68 and 0.84 microg.ml(-1), respectively. The tissue concentrations of amiodarone amounted to 13.2 and 28.3 microg.g(-1), respectively, in the atria and to 13.0 and 40.8 microg.g(-1), respectively, in the ventricles. The distribution of the drug and its metabolite were similar in the right and left ventricles. There was a good correlation between myocardial concentration of amiodarone and desethylamiodarone and the cumulative ingested dose of amiodarone. Tissue drug concentrations correlated only poorly with plasma amiodarone or desethylamiodarone levels. The highest drug levels were measured in the epicardial fat tissue, where the ratio of amiodarone 105 microg.g(-1) to desethylamiodarone 32 microg.g(-1) was reversed (3.3 compared with 0.29 in the ventricles). Thus, amiodarone concentrations in epicardial fat were approximately 10 times higher than myocardial and 150 times higher than plasma levels. Our data confirm the slow equilibrium of amiodarone and desethylamiodarone concentrations between plasma and myocardium. Myocardial tissue concentrations of desethylamiodarone and, to a lesser degree, amiodarone correlate with the cumulative ingested dose of amiodarone. Monitoring of the total cumulative dose may be more relevant clinically than monitoring plasma levels. These results support the clinical practice of reducing the maintenance dose of amiodarone in patients who are on long-term treatment.

Acute antiarrhythmic effects of intravenously administered amiodarone on canine ventricular arrhythmia.

We investigated antiarrhythmic effects of intravenously (i.v.) administered amiodarone using four canine ventricular arrhythmia models. Bolus injections of amiodarone 3 mg/kg suppressed epinephrine (EPI)-induced arrhythmia and 5-mg/kg bolus injections of amiodarone suppressed digitalis- and two-stage coronary ligation-induced arrhythmia models, but the antiarrhythmic effects did not correlate with the amiodarone plasma concentrations. The infusion of amiodarone 6.67 mg/kg/h did not prolong the QTc interval or produce antiarrhythmic effects in coronary ligation and reperfusion experiments. Amiodarone significantly decreased the mean blood pressure (MAP), and this effect lasted throughout the observation period. The results indicate that the antiarrhythmic effects of intravenously administered amiodarone may not be due to its class III action, but to other actions, such as class I, II and IV actions.

Antiadrenergic cardiovascular adverse effects of high-dose amiodarone loading regimen

A 55-year-old patient with inferior wall infarction was treated effectively for ventricular tachycardia with high-dose oral amiodarone loading regimen (5 g within 16 hours). Serial pharmacokinetic studies demonstrated a rapid temporary increase in amiodarone plasma concentration to a maximum of 3.40 μg/ml 17 hours after initiation of therapy followed by a return to normal plasma concentration within 8 hours. During fast drug evasion the patient developed acute low-output syndrome with syncope successfully controlled with intravenous catecholamine administration. Our findings suggest that the cardiovascular collapse was caused by the non-competitive adrenoceptor antagonism of amiodarone resulting in secondary autonomic insufficiency.

Efficacy and safety of short intravenous amiodarone in supraventricular tachyarrhythmias

The safety and efficacy of short intravenous therapy with amiodarone were evaluated in 44 patients (24 males, 20 females), aged 21–84 years, with supraventricular tachyarrhythmias newly arisen in less than 24 hours. The study group consisted of 15 patients with paroxysmal supraventricular tachycardia, 8 patients with atrial flutter and 21 patients with atrial fibrillation. They were treated with a single infusion of amiodarone up to 2 hours after the restoration of a stable sinus rhythm, or up to a maximum dose of 2400 mg in 24 hours. Our study shows that 88.6% of all supraventricular tachyarrhythmias reverts to sinus rhythm in less than 24 hours: 100% of paroxysmal supraventricular tachycardia, 75% of atrial flutter, and 85.7% of atrial fibrillation. Intravenously administered amiodarone proves to take effect rapidly (0.5 to 22 hours). The plasma amiodarone concentrations at sinus rhythm restoration showed a wide range (405–3800 ng/ml). Piecewise analysis suggested that the probability of sinus rhythm was 14.4-fold greater in paroxysmal supraventricular tachycardia. No linear statistical relationship was detectable between the log-dose-body mass index and log-QTc. Total amiodarone dose and left atrial volume are inversely correlated with a statistically significant difference. The toxicity in our short intravenous course with amiodarone was not relevant. We conclude that short high-dose intravenous amiodarone shows efficacy and safety in all newly occurring supraventricular tachyarrhythmias.

Chylous Transport of Amiodarone

A patient receiving amiodarone for longstanding ventricular dysrhythmias presented with idiopathic chylothorax. During drainage of chylothorax for pleurodesis, serial plasma amiodarone concentrations declined while pleural fluid concentrations remained stable. Chylous transport of amiodarone and other lipid-bound drugs should be recognized to avert complications during chylothorax drainage.

Pharmacology and Pharmacokinetics of Amiodarone

Amiodarone is a unique antiarrhythmic agent originally developed as a vasodilator. Classified electrophysiologically as a Type III antiarrhythmic, it also has both nonspecific antisympathetic and direct, fast channel-membrane effects. Hemodynamic effects of orally administered amiodarone (a negative inotropic agent) are usually negligible, and are usually compensated for by induced vasodilation. Effects on thyroid and hepatic function may help to explain some of the unique pharmacologic as well as toxicologic effects of the drug. Amiodarone is poorly bioavailable (20-80%) and undergoes extensive enterohepatic circulation before entry into a central compartment. The principal metabolite, mono-n-desethyl amiodarone is also an antiarrhythmic. From this central compartment, it undergoes extensive tissue distribution (exceptionally high tissue/plasma partition coefficients). The distribution half-life of amiodarone out of the central compartment to peripheral and deep tissue compartments (t1/2 alpha) may be as short as 4 hours. The terminal half-life (t1/2 beta) is both long and variable (9-77 days) secondary to the slow mobilization of the lipophilic medication out of (primarily) adipocytes. A pharmacokinetically based loading scheme is described, and data suggesting a role for routine amiodarone plasma levels are presented.

Relationship between myocardial amiodarone concentration and antiarrhythmic effect in dogs with myocardial infarction and electrically induced ventricular arrhythmias

The relationship between the antiarrhythmic effect of amiodarone and its myocardial concentration was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia or ventricular fibrillation. Three groups of animals (n = 10/group) received amiodarone, 40 mg.kg-1.day-1 (low-dose amiodarone), amiodarone 60 mg.kg-1.day-1 (high-dose amiodarone), or no amiodarone (control group). After 1 week of treatment, programmed electrical stimulation was repeated, and plasma and myocardial amiodarone and desethylamiodarone concentrations were measured. In the control group, sustained ventricular tachycardia or ventricular fibrillation was induced in six dogs (p = NS) when compared with baseline data. In the low-dose amiodarone group, sustained ventricular tachycardia or ventricular fibrillation was induced only in two dogs after 1 week of treatment (p less than 0.01 vs. baseline data). Sustained ventricular tachycardia or ventricular fibrillation was induced in seven dogs after treatment with high-dose amiodarone (p = NS vs. baseline data). Plasma amiodarone concentration in the low-dose amiodarone group (2.54 +/- 1.95 micrograms/mL) was significantly less (p less than 0.01) than that in the high-dose amiodarone group (4.64 +/- 1.66 micrograms/mL). Similarly, the plasma desethylamiodarone in the low-dose amiodarone group (0.32 +/- 0.16 microgram/mL) was significantly less (p less than 0.001) than that in the high-amiodarone dose group (0.56 +/- 0.23 microgram/mL). The myocardial amiodarone concentration in the low-dose amiodarone group (49.7 +/- 23.1 micrograms/g) was significantly lower (p less than 0.001) than that in the high-dose group (98.4 +/- 32.1 micrograms/g).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Amiodarone on Serum T3and T4Concentrations in Hyperthyroid Patients Treated with Propylthiouracil

Amiodarone (Cordarone) has been proven to be useful in the management of atrial fibrillation. However, because of a large iodine content, this drug is not used in this complication of thyrotoxicosis. We previously have observed a greater fall in serum T3 and T4 concentrations in hyperthyroid patients treated with amiodarone and methimazole than with methimazole alone. In the present study, we determined whether the addition of amiodarone to propylthiouracil (PTU) could improve the levels of circulating thyroid hormones in hyperthyroid patients, and we assessed the release of iodide from amiodarone by measuring the 24 h urinary iodine excretion. Twelve hyperthyroid patients were treated either with PTU, 600 mg daily for 10 days (group PTU), or with amiodarone (A), 1200 mg daily for 3 days in addition to PTU (group A-PTU). Basal serum T4, T3, and rT3 concentrations (mean +/- SEM) were respectively 206 +/- 13 nmol/L, 5.13 +/- 0.8 nmol/L, and 81 +/- 7 ng/dL for group PTU and 238 +/- 39 nmol/L, 4.73 +/- 1.06 nmol/L, and 84 +/- 12 ng/dL for group A-PTU (NS). In group A-PTU, plasma amiodarone peaked on day 3 (mean +/- SEM: 0.48 +/- 0.11 mg/L), and urinary iodine reached 5.27 +/- 1.28 mg/day on day 5. The fall in serum T3 and the increase in serum rT3 concentrations were significantly greater in group A-PTU than in group PTU (ANOVA, p less than 0.05). In group A-PTU, the minimal serum T3 concentration was observed on day 5 of treatment (28 +/- 6% of the pretreatment values).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial amiodarone and desethylamiodarone concentrations in patients undergoing cardiac transplantation

Myocardial amiodarone and desethylamiodarone concentrations were measured at multiple sites in the explanted heart in four patients who underwent cardiac transplantation. Patients were taking amiodarone, 200 to 400 mg/day (mean 300 +/- 115), for 88 to 428 days (mean 229 +/- 148). The mean cumulative dose was 58 +/- 21.3 g. Plasma amiodarone concentration in three subjects was 204, 312 and 419 ng/ml and desethylamiodarone concentration was 268, 513 and 880 ng/ml, respectively. Significant interindividual variability in myocardial concentrations of amiodarone and desethylamiodarone was observed (p less than 0.05). Mean myocardial amiodarone concentration ranged from 4 +/- 1.0 to 29 +/- 17.2 micrograms/g (p less than 0.05); mean desethylamiodarone concentration ranged from 22 +/- 8.8 to 141 +/- 102.5 micrograms/g (p less than 0.05). At each site, save for fat, myocardial desethylamiodarone concentration was higher than amiodarone concentration. Greater intraindividual variability was observed in myocardial desethylamiodarone compared with amiodarone concentration particularly in septal and scar tissue (p = NS). No significant relation was found between myocardial concentration and duration of treatment. In patients with significant ventricular disease, usefulness of plasma amiodarone and desethylamiodarone concentration to estimate myocardial concentration is limited by intra- and interindividual variability.

Plasma amiodarone levels do not change significantly with time once steady state has been achieved

Plasma amiodarone levels do not change significantly with time once steady state has been achieved

Antiarrhythmic Effect of Chronic Oral Amiodarone Treatment in Dogs with Myocardial Infarction and Reproducibly Inducible Sustained Ventricular Arrhythmias

The antiarrhythmic effect of an 8-week oral amiodarone regimen was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Eighteen dogs were randomly assigned to receive either amiodarone, 40 mg/kg/day for 10 days, followed by 30 mg/kg/day for 4 days and then 20 mg/kg/day for 6 weeks (N = 9), or placebo (N = 9). Programmed electrical stimulation was conducted weekly in the two treatment groups. Plasma concentrations of amiodarone and desethylamiodarone were determined weekly, and their myocardial concentrations in the noninfarcted and infarcted regions of the left ventricle were measured at the end of the study. Suppression of inducible arrhythmias was observed at weeks 1,3-7, and 8 in the amiodarone-treated dogs, whereas no suppression occurred in the placebo-treated group. Plasma amiodarone concentration was maximal at 2.5 +/- 1.4 micrograms/ml at week 2, decreased to 1.9 +/- 1.1 micrograms/ml at week 3, and remained steady thereafter. Plasma desethylamiodarone concentrations were in the range of 0.2 +/- 0.1 to 0.4 +/- 0.2 microgram/ml from weeks 1 through 8. Myocardial amiodarone and desethylamiodarone concentrations in the noninfarcted region of the left ventricle were 34.0 +/- 15.8 and 20.8 +/- 7.8 micrograms/g, respectively, at the end of the study. The lack of antiarrhythmic effect of amiodarone at week 2 coincided with the highest plasma amiodarone concentration. The data indicate that this dog model of ventricular arrhythmias is useful for studying the antiarrhythmic action of amiodarone.

Stability of plasma amiodarone levels during chronic oral therapy

The variability of plasma amiodarone levels in 51 patients receiving chronic oral therapy over 4-53 (median 19) months was examined; 3-14 (median 5) plasma samples were obtained. After a loading dose, most patients received either 200 mg or 400 mg a day. Mean plasma amiodarone concentration was 1.2 +/- 0.6 mg/l and mean plasma desethylamiodarone concentration was 1.2 +/- 0.5 mg/l. No relationship was seen between height and weight and plasma concentrations. Dose was a significant predictor of plasma level (p less than 0.01) although it was a poor predictor of steady state amiodarone concentration.

Individual variability of amiodarone distribution in plasma and erythrocytes: implications for therapeutic monitoring.

The complexity of amiodarone disposition in blood and tissues gives rise to difficulty in determination of optimal therapeutic monitoring strategies. We have defined the within-patient variability of plasma and erythrocyte amiodarone and desethylamiodarone concentrations and electrocardiogram intervals [PR and corrected QT (QTc)] in 27 patients each sampled on three to four occasions during long-term stable amiodarone therapy. All individual repeated measurements were included in the concentration-effect analysis. The mean within-patient coefficients of variation for amiodarone and desethylamiodarone were significantly greater in erythrocytes, 46.0 and 24.5%, respectively, compared with plasma, 12.7 and 12.3%. Amiodarone and desethylamiodarone were significantly greater in erythrocytes, 46.0 and 24.5%, respectively, compared with plasma, 12.7 and 12.3%. Amiodarone and desethylamiodarone were strongly correlated (r = 0.29 p less than 0.004). There was a 10-fold variability in erythrocyte amiodarone for a given plasma level. These data emphasize the highly variable cellular distribution of amiodarone and desethylamiodarone in the same patient on stable dosage over time. Plasma amiodarone was significantly correlated with dosage (r = 0.98), and percent change in QTc, (r = 0.56, p less than 0.0001), but there was a fourfold variation in plasma amiodarone for a given QTc. Side-effect frequency was not related to plasma or erythrocyte amiodarone or desethylamiodarone concentrations. A clinically useful relationship between plasma concentration and effect could not be consistently demonstrated for amiodarone in the same individual during stable dosage.

The digoxin-amiodarone interaction

To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4-8 months. Mean (+/- SD) peak plasma digoxin concentration rose from 1.55 +/- 0.6 microgram /1 prior to amiodarone therapy to 2.85 +/- 1.3 micrograms/1 after 1 week of combined therapy (p less than 0.01). Mean AUC also rose from 7.2 +/- 2.1 micrograms/1.h to 12.1 +/- 6.4 micrograms/1.h (p less than 0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4-8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses. This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.

Efficacy of intravenous amiodarone as short-term treatment for refractory ventricular tachycardia

The antiarrhythmic efficacy and safety of intravenous amiodarone were evaluated in 13 patients with recurrent sustained ventricular tachycardia. All patients had been refractory to at least three prior antiarrhythmic agents (mean, 3.3 per patient), and 11 had multiple direct current cardioversions. Intravenous amiodarone suppressed sustained tachycardia in seven patients; the concurrent use of procainamide resulted in suppression in two additional patients. Ventricular tachycardia recurred in three patients, two within 2 hours of initiation of amiodarone. Adverse effects necessitated the discontinuation of amiodarone in one patient because of significant hemodynamic deterioration. The use of intravenous amiodarone was associated with a significant fall in heart rate and cardiac output. Plasma amiodarone levels were high after initial bolus loading but declined to low or less than therapeutic levels within 60 minutes. Thus although we found intravenous amiodarone to be effective in the short-term treatment of refractory ventricular tachycardia, administration of amiodarone can be associated with significant hemodynamic deterioration. The dosing protocol used should be modified to a lower initial bolus and a higher early maintenance infusion rate.

Relation between amiodarone and desethylamiodarone plasma concentrations and electrophysiologic effects, efficacy and toxicity

Because the value of monitoring amiodarone plasma concentrations remains undefined, this study was performed to evaluate its role during the management of patients receiving amiodarone. The early electrophysiologic effects of amiodarone were assessed in 40 consecutive patients with coronary artery disease and sustained ventricular tachycardia or fibrillation who underwent electrophysiologic studies and measurement of amiodarone plasma concentration before and 29 +/- 15 (mean +/- SD) days after initiation of therapy. Amiodarone and desethylamiodarone plasma levels did not correlate with changes in either sinus cycle length, QTc interval, ventricular effective refractory period, AH and HV intervals or ventricular tachycardia cycle length. Amiodarone and desethylamiodarone plasma concentrations and the effects of the drug on conduction intervals or right ventricular effective refractory periods were not related to suppression of arrhythmia induction by ventricular stimulation after 1 month of therapy. The relation between amiodarone plasma concentrations and both toxicity and efficacy during long-term therapy were prospectively assessed in a larger series of 114 consecutive patients with either symptomatic supraventricular or ventricular arrhythmias who were followed up on long-term amiodarone therapy for 26 +/- 15 months. Sixty-three patients (55%) had one or more adverse effects attributed to amiodarone. By life-table analysis, 40, 69 and 80% of patients had experienced an adverse reaction after 1, 2 and 3 years of therapy, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between the QT interval and plasma amiodarone concentration in patients on long-term therapy.

We have studied 27 patients on long-term treatment (6-60 months) with amiodarone (dose range 350 mg per week to 2800 mg per week) to ascertain whether the corrected QT interval could predict plasma amiodarone or plasma desethylamiodarone concentration. The patients were assessed on three or four occasions one month apart. There were positive correlations for delta % QTc and plasma amiodarone and delta % QTc and plasma desethylamiodarone. There was approximately a four-fold variation for delta % QTc and plasma amiodarone. This variation was not accounted for by between-occasion variation in the QTc interval, as the coefficient of variation was 2.1%. In six of the patients delta % QTc either decreased or did not change. delta % QTc is not a reliable predictor of plasma amiodarone concentration in the individual patient over time.