Pharmacokinetics of flecainide in patients with cirrhosis of the liver.

The pharmacokinetics of flecainide were studied in six patients with cirrhosis of the liver and in six healthy subjects after a single 2 mg/kg intravenous dose. Hepatic biotransformation capability before flecainide dosing was assessed by antipyrine challenge. The mean plasma antipyrine t1/2 for patients (42.2 hours) was longer (p less than 0.01) than that for subjects (11.7 hours). For control subjects, the plasma t1/2 of flecainide (9.5 hours) was shorter (p less than 0.01), plasma clearance (9.1 ml/min/kg) was faster (p less than 0.01), and volume of distribution (7.5 L/kg) was smaller (p less than 0.05) compared with corresponding values in patients. Renal clearance did not differ (p greater than 0.05) between the two groups. The mean ratio of renal clearance to plasma clearance for subjects (0.4) was smaller (p less than 0.05) than that for patients. The slower rate of flecainide elimination from plasma in patients is likely due to reduced hepatic biotransformation. In patients with cirrhosis, plasma levels of flecainide may accumulate to unacceptably high levels with usual dosage regimens.

Flecainide pharmacokinetics after multiple dosing in patients with impaired renal function.

STUDY OBJECTIVE: To determine the pharmacokinetics of oral flecainide acetate after single and multiple doses in patients with impaired renal function. DESIGN: Paired study of single followed by multiple oral doses. SETTING: PATIENTS enrolled in a Veterans Administration Hospital renal subspecialty clinic and dialysis unit. PATIENTS: Twenty men and one woman between the ages of 33 and 74 years with impaired renal function including ten patients with end-stage renal disease receiving maintenance hemodialysis. INTERVENTIONS: All patients received a single, oral, 200-mg dose of flecainide acetate followed by sequential venous blood sampling. Seven to 14 days after the single-dose study, each patient received 100 mg of flecainide acetate by mouth every 12 hours or every 24 hours for 10 days. Venous blood samples were drawn periodically during multiple dosing and sequentially after the last dose. Measurements and primary results: Peak flecainide acetate concentrations (micrograms/L) were 330 +/- 104 micrograms/L (mean +/- SD) after the single dose and 687 +/- 505 micrograms/L after multiple doses. Time to peak occurred at 3.3 +/- 2.3 hours and 2.7 +/- 1.2 hours after single and multiple doses, respectively. The apparent volume of distribution was 8.2 +/- 2.9 L/kg and 9.2 +/- 5 L/kg after single and multiple dose studies, respectively. Plasma elimination half-life after the single dose (20.4 +/- 9.0 hours) was significantly shorter (P less than .001) than after multiple doses (37.8 +/- 39.7 hours), as was total body clearance: 391 +/- 154 mL/min versus 302 +/- 194 mL/min. There were no statistically significant differences between pharmacokinetic measurements determined for patients on chronic hemodialysis when compared with nondialysis patients during the multiple-dose study.(ABSTRACT TRUNCATED AT 250 WORDS)

The development and testing of intravenous dosing regimens: application to flecainide for the suppression of ventricular arrhythmias.

A two-part pharmacokinetic approach was used to prospectively develop and test intravenous flecainide infusion regimens for the acute therapy for ventricular arrhythmias. Initially, each of nine known responders to oral flecainide was given a rapid flecainide infusion to characterize pharmacokinetic parameters and determine the minimum effective concentration for each patient. These data were used to calculate individually appropriate three-stage flecainide infusions of predetermined durations in eight patients. The three-stage infusions (0.15 +/- 0.02 mg flecainide acetate/kg/min for 5 minutes, 0.046 +/- 0.004 mg/kg/min for 60 minutes, and 0.31 +/- 0.05 mg/kg/hr for 5 to 47 hours; mean +/- SE) resulted in 95% +/- 0.1% suppression of ventricular ectopic depolarizations. Based on these results, six additional patients received a uniform infusion regimen (0.1 mg/kg/min for 5 minutes, 0.025 mg/kg/min for 2 hours, and 0.25 mg/kg/hr for 46 hours). Supplemental doses of 0.25 mg/kg were given (four doses per patient). With this protocol, ventricular ectopic depolarizations were 82.6% +/- 8.5% suppressed. Measured plasma flecainide concentrations were not significantly different from those predicted by pharmacokinetic models. A prompt and sustained antiarrhythmic effect was obtained with an intravenous regimen of flecainide determined by a prospective pharmacokinetic approach. However, the dosages developed in this study may have to be modified for patients with impaired cardiac or renal function.

Oral flecainide pharmacokinetics in patients with impaired renal function.

The pharmacokinetics of flecainide acetate were studied in 20 patients with varying degrees of renal impairment following a single oral dose. The patients were divided into two groups, on the basis of renal creatinine clearance (CLCR), for statistical and kinetic analysis. Patients with a CLCR between 4 and 41 mL/min/m2 were designated group 1 and those below 4 mL/min/m2 or unmeasurable because of lack of urine output were designated group 2. In both groups peak plasma flecainide concentrations, time to peak concentrations, and apparent volume of distribution (Vd) were similar to those reported in healthy subjects with normal renal function. The mean flecainide plasma elimination half-lives from both groups 1 and 2 were longer than those previously reported by several investigators in normal subjects. Nine patients in group 1 and seven patients in group 2 had half-lives within the range reported in healthy subjects. Therefore, CLCR alone is not a good predictor of plasma elimination half-life following a single oral dose of flecainide. Although renal clearance of flecainide is significantly reduced in end-stage renal disease (ESRD), total plasma clearance of flecainide (CLflec) was not reduced to the same degree, although there was a significant, modest correlation with CLCR. Less than 1% of the administered oral dose of flecainide was removed during hemodialysis. The relationship between dosage and plasma elimination half-life in patients with ESRD needs further study to evaluate possible dose-dependent kinetics.

The effect of flecainide acetate, a new antiarrhythmic, on plasma digoxin levels.

The possible effect of oral flecainide acetate on steady-state digoxin levels was assessed in 15 healthy men. Each volunteer received digoxin 0.25 mg daily (8 AM) for 22 consecutive days and flecainide 200 mg bid (8 AM and 8 PM) on days 11 through 15. Plasma digoxin and flecainide levels were measured by radioimmunoassay and gas-liquid chromatography methods, respectively. Flecainide levels were within the range associated with suppression of premature ventricular contractions in patients. Mean plasma digoxin levels just before the 8 AM dose were 0.46 ng/mL on days 9 and 10 (baseline), 0.57 ng/mL (P less than .05) on day 13, and 0.49 ng/mL (not significant [NS]) on day 15. Compared with a mean six-hour postdose baseline digoxin level of 0.58 ng/mL, postdose levels were 0.62 ng/mL (NS) and 0.65 ng/mL (P less than .05) on days 13 and 15, respectively. On an average for each subject, predose and six-hour postdose digoxin levels increased by 24 +/- 35% and 13 +/- 19%, respectively, during coadministration. The changes in electrocardiographic intervals and vital signs that occurred during concomitant drug administration were not clinically significant although a slight prolongation of the PR interval was noted in some subjects. Unless plasma digoxin levels are in the upper end of the therapeutic range, changes in magnitude as observed in this study should be clinically inconsequential for most patients.

Biotransformation and elimination of 14C-flecainide acetate in humans.

The metabolism of 14C-flecainide acetate, a new antiarrhythmic, was investigated in four healthy human subjects, after a single, 200-mg oral dose. The cumulative recovery of radioactivity ranged from 81 to 90% (mean, 86%) in urine and from 4 to 6% (mean, 5%) in feces; thus, flecainide does not appear to undergo extensive biliary excretion, unless reabsorption occurs after biliary elimination. The cumulative excretion in urine of unchanged flecainide ranged from 35 to 50% (mean, 42%) of the dose and was essentially complete by 72 hr postdose. Peak plasma levels of radioactivity (524 to 848 ng eq/ml) and of unchanged flecainide (214 to 281 ng/ml) were attained at 2 to 3 hr postdose. The average half-life for the disappearance of unchanged flecainide from plasma was about 16 hr; disappearance of total metabolites from plasma was only slightly slower. Radiomonitored TLC analysis showed that urine contained two major metabolites and two or three minor ones; both major metabolites were extensively conjugated. By TLC, NMR, and mass spectral comparisons to reference compounds, the two major urinary metabolites were shown to be meta-O-dealkylated flecainide and the meta-O-dealkylated lactam of flecainide. Most of the radioactivity in urine was accounted for by flecainide and the two major metabolites.

Metabolism of flecainide.

After oral administration in healthy human subjects, flecainide absorption is prompt (average peak level at 3 to 4 hours) and nearly complete (at least 90%); flecainide does not appear to undergo consequential presystemic biotransformation. Oral absorption in patients with cardiac arrhythmias, renal disease and congestive heart failure (CHF) is also good. Plasma levels of flecainide are proportional to dose within the therapeutic range. Neither food nor antacid affect the extent of flecainide absorption. In healthy subjects, the plasma half-life of unchanged flecainide is relatively long (mean 13 hours after single doses and 16 hours after multiple dosage). For patients with ventricular premature complexes, the half-life is longer (mean 20 hours), and twice-daily oral dosage is effective. The rate of flecainide elimination from plasma may possibly be reduced in older patients. Overall, the plasma pharmacokinetics of flecainide appear to be reasonably linear (not dose- or concentration-dependent). In humans, most (mean 86%) of a single oral dose is excreted in urine as flecainide and its metabolites; only a small portion (mean 5%) is found in feces. Thus, flecainide does not appear to undergo extensive biliary excretion. A substantial portion (mean 27%) of a dose is excreted in urine as unchanged flecainide. Under alkaline urinary conditions, flecainide elimination may be decreased. Only 2 major and 2 or 3 minor metabolites are found in human urine. The 2 major urinary metabolites possess little or no detectable antiarrhythmic activity and are also the major metabolites present in human plasma (primarily conjugated); since free metabolite levels are very low in plasma, metabolites are not likely to contribute any consequential pharmacologic activity. The rate of flecainide elimination from plasma is somewhat slower in patients with moderate renal failure and in patients with CHF than that for healthy persons, and is markedly slower in some patients with end-stage renal disease. Urinary excretion of unchanged flecainide is somewhat less in moderate renal patients and is markedly less in end-stage renal patients, but is not altered in CHF patients. Dosage should be reduced in patients with more severe renal disease and, if indicated, in some CHF patients. Hemodialysis is not an effective means for removal of unchanged flecainide, but does provide more substantial removal of metabolites. Flecainide is not extensively bound (mean 40%) to human plasma proteins in vitro and binding is independent of total drug level.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma concentrations of flecainide acetate, a new antiarrhythmic agent, in humans.

Flecainide, a new antiarrhythmic agent, was given to eight healthy men to ascertain plasma drug levels and to assess tolerance for the drug. Each subject received a single intravenous (IV) dose (0.5, 1, 1.5, or 2 mg/kg) of flecainide, and plasma levels of unchanged flecainide were measured by gas-liquid chromatography. After an initial rapid distribution phase, the drug's plasma half-life (terminal elimination phase) ranged from seven to 15 hours (mean, 11 hours); half-life was apparently independent of dose level. Immediately after IV administration, the relatively high plasma drug levels seen during the short distribution phase were associated with minor and transient side effects in some subjects receiving the two higher doses; overall, the drug was well tolerated. Plasma flecainide levels 60 minutes after administration (after distribution) ranged from 52 to 300 ng/ml and were reasonably proportional to dose level. The drug's relatively long plasma half-life in humans indicates that plasma levels will be maintained for prolonged periods; thus flecainide should provide sustained therapeutic activity in patients with cardiac arrhythmias.

Measurement of flecainide acetate in human plasma by an extraction spectrophotofluorometric method.

A fluorometric method for the quantitation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide acetate (R-818, flecainide acetate) in human plasma has been developed. The minimum quantifiable concentration of flecainide acetate by this method is 25 ng/ml with a 2 ml plasma sample; a slightly modified procedure which also requires the use of a microcell in the spectrophotofluorometer further increases the maximum sensitivity to 12.5 ng/ml. The precision, expressed as relative standard deviation is 2.9, 0.7, 5.6, 3.5, and 4.3% for 75, 150, 250, 500, and 700 ng flecainide acetate/ml, respectively. The accuracy, expressed as relative error, is -6.7, -3.3, -0.4, +4.4, and -0.4%, respectively, for the corresponding concentrations specified above. The relative standard deviations for the inter-day variation are 19, 7, 9, 9, 8, 10, 13, 12, and 9% for the 25, 50, 100, 200, 300, 400, 600, 800, and 1000 ng/ml standards, respectively. Preliminary data indicate that propranolol and quinidine interfere with this method while procainamide, disopyramide, hydralazine, methyldopa, diazepam, hydrochlorothiazide, and sulfinpyrazone exhibit little or no interference. The results of the analyses of clinical samples by the fluorometric method agree well with an established GLC method. Thus, the quality of the fluorometric method is considered adequate for estimating plasma flecainide acetate levels during drug therapy in most non-research settings, if careful consideration is given to possible interference by other drugs.

Suppression of ventricular ectopic depolarizations by flecainide acetate, a new antiarrhythmic agent.

Flecainide acetate, a new antiarrhythmic agent, was given orally to 11 hospitalized patients with chronic high-frequency ventricular ectopic depolarizations. Drug effectiveness was evaluated with a dose-ranging single-blind protocol, which included placebo control and washout periods. Twice-daily dosing (average daily dose 436 mg) completely suppressed all ventricular ectopic activity in five of 11 patients; average suppression in the 11 patients was 96.3%. Complex ventricular arrhythmias, which were present in all 11 patients during the placebo control period, were completely suppressed in eight patients and markedly suppressed in the other three patients during flecainide therapy. Ejection fraction and velocity of circumferential fiber shortening measured by M-mode echocardiography did not change significantly during flecainide dosing. Ventricular arrhythmias returned in all patients during the placebo washout period. During subsequent outpatient therapy with flecainide, significant suppression was present after 1 and 2 weeks of treatment (94.4% and 93.3%, respectively). Drug elimination was slow (average plasma half-life 20 hours). Ninety-five percent suppression of ventricular ectopic depolarization during dosing and 5% reappearance of arrhythmias during washout occurred with flecainide concentrations of 200-800 ng/ml. Side effects occurred in five of 11 patients, but did not require discontinuation of the drug. These results indicate that flecainide is a very effective antiarrhythmic agent that merits further clinical investigation.

Relationship between plasma concentrations and suppression of ventricular extrasystoles by flecainide acetate (R-818), a new antiarrhythmic, in patients.

To assess the relationship between plasma levels of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benz-amide acetate (flecainide acetate), a new antiarrhythmic, and the suppression of ventricular arrhythmias, a decreasing multiple oral dosage regimen (200 mg b.i.d. to 50 mg b.i.d.) was administered over 12 days to eight patients with chronic ventricular extrasystoles. 1-h ECG recordings and blood samples for plasma flecainide measurements were obtained prior to, during each day of dosage, and post-drug. Maximum plasma levels observed with the higher doses range from 413 to 789 ng/ml (mean 637 ng/ml); these levels are well tolerated and are associated with essentially complete (greater than 95%) suppression of arrhythmias. As dose is decreased, plasma levels decline and the arrhythmias progressively return. The lowest plasma levels associated with essentially complete suppression of ventricular extrasystoles on two consecutive days range from 217 to 414 ng/ml (mean 317 ng/ml); levels below about 230 ng/ml are associated with the initial substantial reappearance (less than 70% suppression) of arrhythmias. These data suggest that the minimum therapeutic plasma levels of flecainide for ventricular extrasystoles range from about 200 to 400 ng/ml and that no consequential side effects are associated with plasma levels two-fold higher than these minimum levels.

Oral flecainide acetate for the treatment of ventricular arrhythmias.

The antiarrhythmic efficacy and safety of oral flecainide acetate were assessed during a controlled, short-term dosage-maintenance study. Thirteen patients with chronic ventricular ectopy entered a placebo control period, and 11 with persistent, frequent (greater than 600 per 12 hours) premature ventricular complexes (PVCs) advanced to drug therapy. Of 10 patients completing a trial of different doses, nine responded completely, with a mean PVC suppression of 98,3 per cent. Repetitive PVCs were eliminated. The mean effective dose was 189 mg per 12 hours, and the effective plasma concentration before administration of a dose averaged 635 ng per milliliter. One patient responded partially (68 per cent of PVCs suppressed). Flecainide continued to be effective and well tolerated at the end of a two-week outpatient trial in the nine complete responders, maintaining an average PVC suppression of 94.6 per cent. The PR and QRS intervals were mildly prolonged. The echocardiographic ejection fraction was unchanged during treatment. The elimination half-life was long - 18.8 +/- 3.8 hours. Flecainide thus appears to be a highly effective and well-tolerated antiarrhythmic agent with favorable pharmacokinetics.

Monomer release from methacrylate bone cements during simulated in vivo polymerization.

The release of monomer from methylmethacrylate bone cements was studied during immersion in an aqueous environment intended to simulate in vivo polymerization of the material. Monomer release from disk-shaped specimens into an aqueous environment was assayed by gas chromatography. The simulated intracorporal polymerization was carried out under a variety of conditions intended to encompass possible clinical variables. The majority of monomer release occurred within the first 15 min of immersion. Under conditions generally recommended for commercial cements the release into aqueous media was always less than 3% of the total monomer weight. Clinically feasible options of delaying the time from onset of mixing of the cement to insertion into the host resulted in only a 0.7 wt % difference in the amount of released monomer. Measurements for a variety of monomer/powder ratios demonstrated a minimum in the amount of released monomer at a ratio of about 0.4 ml/g. In terms of unit area covered, thin specimens released less monomer than thick specimens.