The effects of cimetidine and ranitidine on the pharmacokinetics of cifenline.

Twelve healthy subjects completed an open single dose study to evaluate the effect of co-administration of cimetidine and ranitidine on the pharmacokinetics of cifenline. Each subject received a single 160 mg dose of cifenline alone, in combination with cimetidine (300 mg four times daily), and with ranitidine (150 mg twice daily). The H2-receptor antagonists were given with breakfast 1 h prior to cifenline dosing and continuing for 48 h. Co-administration of cimetidine significantly increased Cmax (27%) and AUC (44%) and prolonged the half-life (30%) of cifenline. There were no differences in these parameters when ranitidine was co-administered with cifenline. The results of this study suggest that cimetidine, but not ranitidine, lowers the clearance of cifenline by inhibition of hepatic oxidative metabolism.

Bioavailability and kinetics of cibenzoline in patients with normal and impaired renal function.

To test the hypothesis that renal failure alters the disposition of cibenzoline in humans, an absolute bioavailability and elimination kinetic study was performed. We used the simultaneous administration of a stable isotope variant (SASIV). Eight healthy volunteers and eight matched hemodialysis patients each received simultaneously an 80-mg intravenous infusion of 15N-2-cibenzoline and a single 80-mg cibenzoline capsule. Cibenzoline plasma concentrations were assayed by a gas chromatographic-mass spectrometric assay. A compartment-independent kinetic analysis showed a plasma clearance of 707 mL/min and an elimination half-life of 7.3 hours after the intravenous dose in healthy volunteers. In renal-failure patients, cibenzoline clearance decreased to 224 mL/min and half-life increased to 22.4 hours. Decreased plasma clearance was due to decreases in both renal and nonrenal clearance. Absolute bioavailability was 83% and 90% in healthy volunteers and renal-failure patients, respectively. Hemodialysis accounted for only 13% of drug clearance.

Cifenline in the short-term treatment of patients with ventricular premature complexes: a double-blind placebo-controlled study.

To study the efficacy and safety of cifenline (cibenzoline), a new antiarrhythmic agent, we enrolled 46 patients with greater than 700 premature ventricular complexes (VPCs)/24 h in an ambulatory electrocardiography study. During an open-label titration phase, 25 patients showed greater than 75% VPC suppression while receiving 130 mg (15 patients) or 160 mg (10 patients) cifenline twice daily. During a double-blind placebo-controlled phase in 23 of these patients, cifenline was more effective than placebo in controlling VPCs (p less than 0.0001) and VPC pairs (p less than 0.025). A small (0.01 s) increase in QRS duration was observed (p less than 0.05) during cifenline treatment. Adverse experiences included gastrointestinal complaints and dizziness as well as two instances of hypotension and one instance of symptomatic ventricular tachycardia. Cifenline appears to be effective and well tolerated in the treatment of VPCs.

The natural history of benign and potentially malignant ventricular arrhythmias with special reference to nonsustained ventricular tachycardia.

Ambulatory ECG recordings are routinely used to identify patients at increased risk of sudden cardiac death and to monitor changes in ventricular arrhythmias during antiarrhythmic drug therapy. The arrhythmia frequency established during the initial baseline has previously been reported to change during a second placebo monitoring period in patients with non-life-threatening ventricular arrhythmias, but the extent to which this applies to patients with nonsustained ventricular tachycardia has not been examined. To extend these observations to patients with potentially lethal ventricular arrhythmias, we studied 53 patients enrolled in one of two investigational antiarrhythmic drug trials that introduced a second single-blind placebo period (placebo-pulse) an average of 16 months after successful arrhythmia suppression. Thirty-eight of the 53 patients had runs of nonsustained ventricular tachycardia recorded during the initial baseline (placebo I) period, with 63% averaging greater than or equal to 10 runs per day. There was a marked reduction in the arrhythmia frequencies between the two placebo periods: 55% for ventricular premature beats, and 77% for pairs (p less than 0.001, respectively). Of the 38 patients with nonsustained ventricular tachycardia, there was a 72% reduction (892 +/- 531 vs 245 +/- 18 runs of VT/day, placebo I vs II; p = 0.0001), with 32% having total suppression of nonsustained ventricular tachycardia during the second placebo period. The results of this trial extend our previous observations of long-term spontaneous changes in arrhythmia frequency to patients with symptomatic, potentially lethal ventricular arrhythmia and support the recommendation for periodic reassessment of baseline arrhythmia frequency to determine the continued need for antiarrhythmic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of renal impairment on the pharmacokinetics of cibenzoline.

Sixteen subjects completed an open-label study designed to assess the effect of renal impairment on the disposition of cibenzoline. The study included 10 patients with mild or moderate renal impairment creatinine clearance less than 60 ml/min/70 kg) and six healthy subjects in the same age range, each of whom received a single 130 mg oral dose of cibenzoline. The pharmacokinetic parameters observed in the healthy volunteers were similar to those reported previously. Maximum plasma concentration, time of maximum concentration, and apparent volume of distribution after single doses in patients with renal impairment were in the same range as those observed in healthy volunteers. The elimination half-life increased with decreasing renal function from a mean value of approximately 8 hours in healthy volunteers to more than 20 hours in patients with moderate renal impairment. Renal clearance and the fraction of the dose excreted unchanged in the urine decreased with decreasing creatinine clearance. The results of this study suggest that the dosage of cibenzoline should be reduced or the dosage interval increased in patients with reduced renal function to avoid excessive drug accumulation.

Evaluation of dosing interval and optimum dose of cibenzoline.

Fifteen patients with ventricular premature complexes (VPCs) were included in this open study designed to assess the relative efficacy of bid (two times daily) and tid (three times daily) dosing regimens for cibenzoline as compared with qid (four times daily) administration. Patients started therapy with qid administration; this was followed in sequence by tid and bid administration at the maximum effective total daily dose determined during the qid administration. Of the nine patients evaluated for efficacy for suppression of VPCs, eight demonstrated a 75% or greater suppression of VPCs with cibenzoline administered qid (total daily dose of 130-325 mg). This effectiveness was maintained in four patients with a bid regimen and in three with a tid regimen. All four patients who had ventricular tachycardia (VT) had a decrease in the number of VT episodes while receiving cibenzoline (only one of these patients had satisfactory suppression of VPCs at the same dosage regimen). Twelve patients continued to receive extended therapy with cibenzoline for up to two years, as this was considered to be the optimum antiarrhythmic treatment for these patients. Two patients had to be removed from the study and two had the dosage lowered because of adverse reactions (dry mouth, blurred vision, dizziness, congestive heart failure) although in one instance, the congestive heart failure was subsequently considered to be unrelated to cibenzoline. One patient was able to complete the short-term phase of the trial, but was not given extended treatment because of persistent dry mouth. Two patients had treatment discontinued during the extended therapy phase because of adverse reactions (fever, nausea, vomiting, asthenia).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cibenzoline after single and repetitive dosing in healthy volunteers.

Twenty-five healthy, adult male volunteers entered two open-label parallel studies, each designed to define the pharmacokinetics of single and multiple oral doses of cibenzoline. Each volunteer received a single 160-mg oral dose of cibenzoline followed two or three days later by 160 mg of cibenzoline q12h for seven days. Plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for unchanged drug. The apparent half-life following administration of the last dose (9.7 hours) was slightly longer than that observed after the first dose (8.4 hours). Total body clearance and nonrenal clearance were decreased after the last dose compared with the first dose, whereas renal clearance was not significantly altered. After both the first and last dose, the renal clearance greatly exceeded the glomerular filtration rate, suggesting that tubular secretion participates in the renal excretion of cibenzoline. Plasma concentrations from samples collected during the multiple-dose regimen suggest that a slight but statistically significant diurnal variation in the absorption and/or clearance of drug occurred during the course of the study. Overall, the pharmacokinetics of cibenzoline are characterized by a slightly longer half-life during multiple dosing than that observed following a single dose, due to a decrease in the nonrenal clearance. The multiple-dose pharmacokinetics reported herein are consistent with bid dosing for the maintenance of therapeutic plasma concentrations in patients taking chronic therapy.

Pharmacokinetics and pharmacodynamics of intravenous cibenzoline in normal volunteers.

The pharmacokinetics of intravenous (IV) cibenzoline were studied in six healthy male volunteers ranging in age from 51 to 78 years. The subjects received intravenous (IV) cibenzoline 100 mg over 20 minutes, and plasma and urine specimens were collected for 48 hours. Cibenzoline plasma concentrations at the end of the infusion ranged from 730 to 1,420 ng/mL and exhibited triexponential decline thereafter. The following mean model independent pharmacokinetic parameters were calculated from the plasma and urine concentration data: terminal half-life, 9.8 hours (range, 8.5-11.9); plasma clearance, 523 mL/min (range, 387-687); volume of distribution, 445 L (range, 328-506); and renal clearance, 289 mL/min (range, 202-334). Approximately 31% to 59% of the dose was recovered unchanged in the urine in 48 hours. A triexponential pharmacokinetic equation with zero order input was used to curve fit the plasma and urine data, and the model-dependent parameters agreed well with the model-independent estimates. A hysteresis loop was observed in the relationship between cibenzoline plasma concentration and QRS prolongation, indicating an initial lag between plasma concentration and effect after IV administration. Based on these results, the following preliminary dosing regimen was proposed to rapidly achieve and maintain therapeutic plasma concentrations equal to or slightly greater than 200-400 ng/mL: 0.25 mg/kg/min IV bolus over one minute followed by 1-1.5 mg/kg/hr for one hour and 0.2-0.4 mg/kg/hr for long-term infusion.

Antiarrhythmic effects of cibenzoline.

Thirty-three patients with ventricular tachyarrhythmias were referred for evaluation of their arrhythmias using programmed electrical stimulation to guide antiarrhythmic therapy. Cibenzoline succinate, a new antiarrhythmic agent, was compared to procainamide in patients with ventricular tachycardia. Cibenzoline was given intravenously, initially 1.0 mg/kg, then in 1 mg/kg increments to a maximum of 3.0 mg/kg, during electrophysiologic testing. The results were compared to procainamide, which was also administered intravenously to 1000 and then to 1500 mg. Cibenzoline provided protection against ventricular tachycardia induction in 16 of 33 patients. The PR interval increased 13%, QRS duration widened 26%, and QTc interval was prolonged by 7%. There was a 9% fall in mean arterial blood pressure. Procainamide prevented ventricular tachycardia induction in 21 out of 31 patients tested. The PR interval increased 11%, QRS duration widened 27%, and QTc interval prolonged by 8%. Cibenzoline was given orally to 13 patients for chronic treatment. Chronic oral cibenzoline therapy after a mean follow-up of 8.8 months caused a reduction of ventricular ectopy from 666 to 190 beats/hr. Ventricular tachycardia events decreased per Holter monitor recording from 6 to 0.6. Cibenzoline therapy was discontinued in 5 of 13 patients due to break-through arrhythmias (nonsustained ventricular tachycardia on Holter monitor and recurrence of symptoms). Cibenzoline may be an effective antiarrhythmic agent in selected patients.

Pharmacokinetics of oral cibenzoline in arrhythmia patients.

The pharmacokinetics of oral cibenzoline were studied in 30 arrhythmia patients as part of an ascending multiple-dose efficacy study. The elimination half-life of the drug following repetitive dosing ranged from 7.6 to 22.3 hours, with a harmonic mean of 12.3 hours (n = 24), and increased with age and decreasing renal function. The drug exhibited apparent dose proportional and linear pharmacokinetics over the range of doses studied. Multivariate analysis revealed that the patients' age and serum creatinine concentration accounted for 71% of the variability in the range of beta values (terminal elimination rate constant), and that 69.5% of the intersubject variability in the steady-state trough plasma concentrations could be accounted for by the patients' age, weight and serum creatinine concentration. These data suggest that, although there is some intersubject variability in the elimination and accumulation of cibenzoline, much of the variability can be explained by the patients' age, weight and renal function.

The efficacy of cibenzoline in preventing PES induction of ventricular tachycardia in the dog.

The electrophysiologic effects of cibenzoline were studied using programmed electrical stimulation (PES) techniques and were compared to those of quinidine. Cibenzoline, like the conventional class 1 agent quinidine, was effective in preventing arrhythmia induction. Twelve dogs were given 0.02 mg/kg digoxin intravenously for seven days to achieve a steady-state digoxin level. On the eighth day, cibenzoline was administered in incremental doses (0.5 to 10.5 mg/kg) and PES was performed at 30-minute intervals. A mean dose of 2.6 +/- 0.8 mg/kg cibenzoline prevented ventricular tachycardia induction. At this dose, cibenzoline had no significant effect on mean arterial blood pressure, but PR interval increased by 17 +/- 9 per cent, QRS duration by 27 +/- 14 per cent, and the ventricular refractory period (ERP) for the first extra stimulus increased by 35 +/- 9 per cent. A gradual decrease in heart rate and an increase in PR interval and QRS duration was caused by incremental doses of cibenzoline. In six additional animals, quinidine was administered in incremental doses (1 to 30 mg/kg) and PES performed at 30-minute intervals. A mean of 15 +/- 5 mg/kg prevented induction of ventricular tachycardia in five animals. No significant change in heart rate, PR, QRS, and ERP was found at the effective dose.

Single-dose pharmacokinetics and dose proportionality of oral cibenzoline.

The pharmacokinetics of cibenzoline were evaluated in four young healthy volunteers who received ascending oral doses of 65, 97.5, 130, 162.5, 195, 227.5, and 260 mg separated by one week. Cibenzoline plasma concentrations exhibited an apparent biexponential decline following oral absorption. Maximum plasma concentrations and area under the plasma concentration-time curve increased in proportion to the dose. The mean elimination half-life among subjects was independent of dose and ranged from 7.3 to 8.7 hours. Oral clearance ranged from 380 to 575 ml/min and was also independent of dose. A single pharmacokinetic equation was used to adequately describe the plasma concentration data over the entire range of doses for each subject, indicating dose-proportional and linear pharmacokinetics.

Cibenzoline plasma concentration and antiarrhythmic effect.

The relationship between plasma concentrations of cibenzoline and its antiarrhythmic effect was evaluated in patients receiving the drug orally as part of an ascending multiple dose efficacy and tolerance study. Twenty-five patients participated in a 3-day placebo period, 3 days of 32.5 mg cibenzoline every 6 hr, 3 days of 65 mg cibenzoline every 6 hr, 3 days of 81.25 mg cibenzoline every 6 hr, and 3 final placebo days. Arrhythmia frequency was monitored by 24-hr Holter monitoring and blood samples were drawn during and after dosing. Percent reduction in baseline premature ventricular complex (PVC) frequency for the 25 subjects demonstrated considerable interpatient variability in antiarrhythmic response. Cibenzoline plasma concentrations over 300 ng/ml were associated with some decrease in PVC frequency in virtually all cases. The relationship between plasma concentration and PVC frequency was studied more rigorously in eight of the 25 patients and that for ventricular couplet (VC) frequency was studied in six. For these analyses, PVC and VC frequency data were averaged over 6-hr intervals and plotted against trough cibenzoline concentrations. The data from each patient were fitted with a concentration-effect function (Hill equation) by means of least squares regression. With the exception of two extreme values, the concentration corresponding to 90% reduction in PVC frequency (C90) ranged from 215 to 405 ng/ml. In five of the six patients with arrhythmia in whom VC data were also evaluated, the individual C90 for VCs were considerably less than those for PVCs. The agreement between the observed concentration-response relationships and those predicted by curve-fitting the data suggests that the antiarrhythmic effect of cibenzoline is proportional to its plasma concentration, and that the Hill equation provides an accurate mathematic description of the concentration-response relationship.