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Drug interactions with ethmozine® (moricizine HCl)
DrugInteractionswith Ethmozine”(MoricizineHCI) HAROLD L. KENNEDY, MD, MPH, ALASTAIR and R. T. MacFARLAND,
Moricizine HCI, a phenothiazine derivative synthesized in the USSR in 1964, has been shown to be an orally effective antiarrhythmic drug. Moricizine HCI has demonstrated a low incidence of generally mild and transient side effects. Studies of possible drug interaction between it and other drugs most likely to be administered to cardiovascular patients are currently being conducted in US drug trials. Possible interactions between moricizine HCI and cimetidine, and between moricizine HCI and digoxin, are reviewed. The coadministration of moricizine HCI had no effect on the pharmacokinetics of cimetidine; in contrast, cimetidine administration slowed the
M
J. J. WOOD, MD, ChB, MS
elimination of moricizine HCI. The implications of greater therapeutic and/or toxic effects of moricizine HCI must be considered for patients receiving cimetidine and moricizine HCI concomitantly. No significant interactions were observed when monitoring serum levels of moricizine HCI and digoxin in patients with normal renal function receiving digoxin therapy for congestive heart failure or atrial fibrillation. Moricizine HCI in therapeutic dosages (10 mg/kg daily) demonstrated antiarrhythmic efficacy without significant alterations in serum digoxin levels. (Am J Cardiol 1987;60:79F-82F)
an elimination half-life ranging from 8 to 12 hours (mean 4.0).4 Moricizine HCI is extensively (95% to 97%) bound to human plasma proteins and undergoes a first-pass metabolism, where biotransformation is thought to be the predominant route of elimination4 Studies conducted with radiolabeled agents indicate that moricizine HCl has numerous metabolites (at least 18) that are excreted in both urine (4O%] and feces (60%).4Less than 1% of intact moricizine HCl is eliminated in urine or feces in humans4 Early data indicate that patients taking moricizine HCl tend to have higher normalized plasma levels, and that the elimination half-life is longer and more variable than in normal human subjects.4 Relatively few data exist with regard to the pharmacokinetics of moricizine HCl in cardiovascular patients.
oricizine HCl (Ethmozine@)*, a phenothiazine derivative synthesized in the USSR in 1964, has been shown to be an orally effective antiarrhythmic drug in both animals and humansY Moricizine HCl is currently undergoing investigational antiarrhythmic drug trials in the US; its electrophysiologic properties are similar to those of class IB and IC antiarrhythmic agents. Moricizine HCl has notably demonstrated a low incidence of side effects, which are generally mild to moderate in severity, transient and without serious toxicity.Z,3 Studies of possible drug interaction between moricizine HCl and other drugs most likely to be administered to cardiovascular patients (e.g., digoxin, cimetidine, warfarin, etc.] are in their infancy. We will review the early reports of effects of moricizine HCl when concomitant therapy of cimetidine and digoxin is administered.
Drug Interactions Cimetidine and moricizine HCI: The effect of moricizine HCl on cimetidine pharmacokinetics was studied by Biollaz et al5 in 8 normal volunteers 22 to 40 years of age [mean 27.6) who had received no medication for at least 10 days before the study. In the first
Pharmacokinetics Central to any discussion of a new drug with regard to drug interaction is a brief understanding of its normal pharmacokinetics. Studies performed in young human subjects have shown moricizine HCI to be well absorbed by the gastrointestinal tract, with mean peak plasma levels occurring between 0.7 and 1.5 hours and
From the Division of Cardiology, Department of Internal Medicine, St. Louis University Medical Center, St. Louis, Missouri, Address for reprints: Harold L. Kennedy, MD, MPH, Division of Cardiology, St. Louis University Medical Center, 1325 South Grant Boulevard, St. Louis, Missouri 63104.
* Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozinem. 79F
8OF
A SYMPOSIUM:
ETHMOZINEW (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
TABLE I Kinetics of Single Oral Dose of 500 mg Moricizine Alone and with Cimetidine Pretreatment Moricizine HCI AUC oto @J Cm hr/ml) Cl (mllminlkg) T% P (hr.9 Vd (liters/kg)
5.6 f 1.3
38.2 f
10.7
HCI
Moricizine HCI + Cimetidine 7.8 f
1.2”
19.7 f 4.2’
3.4 f 0.5
4.6 f 0.5”
11.1 f 3.1
8.2 f 1.2
AUC = area under the time-concentration curve; Cl = clearance; terminal half-life of elimination; Vd = apparent volume of distribution. Data are mean f standard error of the mean. * p <0.03 compared with before cimetidine administration,
T% =
phase, a single dose of 500 mg moricizine HCl was administered orally after an overnight fast. Blood samples for the measurement of drug levels were drawn immediately before drug administration and at periodic intervals up to 24 hours later. Blood pressure, pulse rate and standard electrocardiographic readings were recorded before and at regular intervals after drug administration. After a l-week washout period, the subjects entered the second phase of the study, in which they took cimetidine 300 mg 4 times daily for 1 week. After 7 days of cimetidine administration, plasma levels of cimetidine were determined during the 6hour dosing interval. While continuing cimetidine administration, a single dose of 500 mg moricizine HCl was again administered and blood samples were collected for the measurement of cimetidine and moricizine HCl. Blood pressure, heart rate and standard electrocardiographic readings were again recorded at the same times as in the first phase of the study. The coadministration of moricizine HCl had no effect on the pharmacokinetics of cimetidine, and the clearance of cimetidine was unchanged. In contrast, cimetidine administration significantly altered the elimination of moricizine HCl, as shown in Table I5 The plasma concentration of moricizine HCI was higher during cimetidine administration, resulting in an increase in the area under the curve and a decrease in clearance (Table I]. Cimetidine slowed the elimination of moricizine HCl, resulting in an increase of the latter agent’s half-life of elimination. Although moricizine HCl appeared to prolong both the PR and QRS intervals, there was no detectable increased prolongation of the PR interval when cimetidine and moricizine HCl were coadministered. Corrected QT intervals were not altered significantly by either moricizine HCl alone or the coadministration of moricizine HCl and cimetidine. Blood pressure and heart rate were unaltered during the trial.5 Thus, the study of Biollaz et al5 showed that moricizine HCl should be added to the list of drugs whose metabolism is inhibited by cimetidine. Previous reports have shown that cimetidine is a potent inhibitor
AGENT
of the metabolism of other antiarrhythmic agents, including propranolo16 and lidocainen7 Biollaz et al5 found that the mean clearance of moricizine HCl was halved when cimetidine was administered for 1 week and was accompanied by a marked increase in moricizine HCl plasma concentration. The subjects with the highest pre-cimetidine drug clearance had the greatest decrease in clearance during cimetidine treatment, indicating considerable interindividual variation. The clinical implications of these findings indicate that patients receiving cimetidine and moricizine HCl simultaneously, a likely combination in the intensive care unit, will have increased moricizine HCl plasma concentrations and potentially greater therapeutic and/or toxic effects. Digoxin and moricizine HCl: Several antiarrhythmic drugs, including quinidine,8 propafenone,g amiodarone,lO verapamilll and diltiazem,12 have been shown to alter serum digoxin levels. Clearly, studies of possible moricizine HCl-digoxin interaction are of current interest. MacFarland et all3 reported on 9 normal male adults between the ages of 22 and 28 years who were studied for moricizine HCl-digoxin interaction. On day 1, each subject received a 1.0 mg intravenous dose of digoxin, and periodic blood samples for digoxin determinations were drawn for the next 4 days. After a l&day washout period, subjects received oral moricizine HCl in a dosage of 12 mg/kg daily (4 mg/kg 3 times daily) for a 12-day period. Blood level determinations for moricizine HCl were then obtained, and subjects received a second 1.0 mg dose of intravenous digoxin immediately after taking their morning dose of moricizine HCl. Blood level determinations for moricizine HCl were again made, and blood and urine collections were made simultaneously for digoxin determinations. No differences were noted in serum digoxin concentrations compared with time curves in the presence of moricizine HCl compared with digoxin concentrations in the absence of moricizine HCl [Table II). Additionally there was no alteration in the profile of moricizine HCl plasma concentration versus time before and after administration of intravenous digoxin .13Therefore, the findings of MacFarland et al indicated that no pharmacokinetic interaction occurs when a single intravenous dose of digoxin is administered with multiple oral doses of moricizine HCl. We recently reported a study of 13 adult patients aged 19 to 72 years (mean 57) who received digoxin therapy for congestive heart failure or atria1 fibrillation as well as moricizine HCl antiarrhythmic therapy.14 All patients had non-life-threatening, hemodynamically stable ventricular arrhythmias, with a mean hourly frequency of 130 ventricular ectopic beats (VEBs), and normal serum creatinine levels. All patients had received oral digoxin as maintenance therapy for at least 14 consecutive days before the study, were deemed clinically stable and required antiarrhythmic therapy for suppression of VEBs. A singleblind, placebo-controlled protocol included 1 week of placebo administration, 2 weeks of moricizine HCl therapy and, after drug therapy, another 1 week of
October 16, 1987
TABLE II
Pharmacokinetics Elimination
THE AMERICAN
of Digoxin (D) in the Absence and Presence of Moricizine
Pt.
D
D+M
D
1 2 3 4 5 6 7 8 9 Mean f SD
37.4 50.2 50.5 52.1 45.3 49.1 49.3 39.1 42.9 45.6”
28.3 36.7 50.4 55.4 46.9 58.4 55.0 38.8 38.6 43.1”
11.70 15.60 14.50 9.20 9.17 7.70 8.22 11.00 14.80 11.3 f 3.01
9.60 12.70 12.50 8.93 9.10 15.80 9.45 11.40 12.40 11.3 f 2.28
0.0 (I)
*WEEK
l,r=0.90
WEEK2
.
r=0.88
l-T 00
0.5
SERUM
1.5 PLACEBO
1.0
DIGOXIN
DURING
20 (ng ml)
2.5
FIGUBE 1. Although mean serum digoxin concentrations tended to be slightly higher (10% to 15%) during moricizine HCI therapy, these differences were not statistically significant. Reproduced with permission from Am Heart J.14
TABLE Ill Mean Serum Digoxin and Moricirine Concentrations During Short-Term Study Pts. W Placebo Moricizine HCI, week 1 Moricizine HCI, week 2 Post-treatment placebo
13 13 13 7
Digoxin (w/ml) 0.91 1.13 1.06 0.83
f f f f
0.12 0.16 0.11 0.27
HCI
Moricizine Wml) 0.00 0.15 0.14 0.00
HCI
L!z0.00 f 0.03 f 0.03 f 0.00
Data are mean f standard error of the mean.
placebo administration. Each patient received a therapeutic dose of oral digoxin (9 patients 0.25 mg, 4 patients 0.125 mg) and moricizine HCl in an approximate dosage of 10 mg/kg daily (equally divided 3 times daily). At the end of each week of placebo, moricizine HCl and post-therapy placebo administrations, blood samples for serum digoxin and moricizine HCl determinations were obtained during oral digoxin administration on 2 consecutive days. Six patients, for medical and logistical reasons, did not enter the post-therapy
Volume 60
81F
HCI (M)
D
DtM
Cl, (ml/min/kg) D
DtM
3.61 3.59 3.31 2.04 2.34 1.81 1.93 3.24 3.98 2.87 f 0.837
* Harmonic mean. From Armitage P, Statistical Methods in Medical Research. Boston: Blackwell Cl = clearance; Cl,, = renal clearance; SD = standard deviation; Vz = volume of distribution. From reference 13 with permission.
^ E y 3.0 w 5- 25 1
OF CARDIOLOGY
Cl (ml/min/kg)
Vz (liters/kg)
Half-Life (hrs)
JOURNAL
3.92 3.99 2.86 1.86 2.24 3.12 1.99 3.40 3.72 3.01 zk 0.824 Scientific,
2.85 3.43 2.67 1.91 2.39 2.54 1.70 1.92 2.52 2.44 f 0.538
DtM 3.35 3.65 2.52 2.45 2.18 2.33 3.07 1.58 2.61 2.64 f 0.630
1971: 364-355.
placebo period. Twenty-four hour ambulatory electrocardiographic recordings for assessing ventricular arrhythmias were obtained on 2 consecutive days at the end of the placebo, treatment and post-treatment placebo periods, respectively.14 There was no significant difference (p >0.05) in serum digoxin or moricizine HCl levels between the placebo or post-treatment placebo and drug treatment periods (Table III]. There was a trend for slightly higher (10% to 15%) mean serum digoxin concentrations during moricizine HCl therapy (Table III). These differences, found during both weeks of moricizine HCI therapy, were neither statistically nor clinically significant. A close correlation of serum digoxin concentrations during the placebo period and during the first (r = 0.90)and second weeks (r = 0.88)of moricizine HCl therapy was noted (Fig. 1). Moricizine HCl concentrations were virtually unchanged during the 2 weeks of antiarrhythmic therapy (Table III]. Moreover, the efficacy of moricizine HCl therapy in suppressing ventricular ectopy during the first and second week of treatment was significant in these patients (Fig. 2). Therefore, serum digoxin concentrations during digoxin maintenance therapy in cardiac patients with normal renal function were found not to be clinically or statistically significantly affected during short-term moricizine HCl therapy. A cautionary note, however, is warranted in extending these observations to patients who may have impaired renal function. Early observations suggest that such patients may potentially manifest higher moricizine HCl levels, with possibly different consequences on serum digoxin levels.
Conclusions A significant interaction has been described between moricizine HCl and cimetidine in normal human subjects. The mean clearance of moricizine HCl was halved when cimetidine was administered 1 week before moricizine HCl; this resulted in a marked increase in moricizine HCl plasma concentration. No significant interactions were observed when monitoring serum levels of moricizine HCl and digoxin in patients with normal renal function receiving digoxin
82F
A SYMPOSIUM:
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
400 300 1 f 200: ‘\ 180-
L ,
11
did not result in either a clinically or statistically significant effect. Acknowledgment: We acknowledge the contributions of Frank I. Marcus, MD, to the patient data base.
References
160.
PLACEBO 142231 (13)
AGENT
WEEK 1 1426 (13)
WEEK 2 1317 (13)
POST-TREATMENT PLACEBO 125257 (7)
VEB:‘hr (NO. OF PATIENTS) FIGURE 2. Moricizine HCI was most effective in suppressing ventricular ectopic beats (VEB) during the 2 treatment weeks. Reproduced with permission from Am Heart J.14
therapy for congestive heart failure or atria1 fibrillation. Moricizine HCI in therapeutic dosages (10 mg/kg daily) demonstrated antiarrhythmic effectiveness without significant alterations of the serum digoxin level. There was a slight elevation (10% to 15%) of serum digoxin levels during 1 and 2 weeks of therapy, but this
1. Morganroth J, Pearlman AS, Dunkman WB, Horowitz LN, Josephson ME, Michelson EL. Ethmozine: a new antiarrhythmic agent developed in the USSR: efficacy and tolerance. Am Heart J 1979;98:621-628. 2. Podrid PJ, Lyakisher A, Lown B, Mazur N. Ethmozine, a new antiarrhythmic drug for suppressing premature ventricular complexes. Circulation 1980;61:450-457. 3. Pratt CM, Yepsen SC, Taylor AA, Mason DT, Miller RR, Quinones MA, Lewis RA. Ethmozine suppression of single and repetitive ventricular premature depolarizations during therapy: documentation of efficacy and long-term safety. Am Heart J 1983;106:85-91. 4. Proceedings of the Ethrriozine Symposium. Montreaux, Switzerland, 1985. Endo Laboratories, Inc., Wilmington, Delaware. 5. Biollaz J, Shaheqn 0, Wood AJJ. Cimetidine inhibition of Ethmozine metabolism. Clin Pharmacol Ther 1985;37:665-668. 6. Feely J, Wilkinson GR, Wood AJJ. Reduction of liver blood flow and propranolol metaQolism by cimetidine. N Engl J Med 1981;304:692-695. 7. Feely J, Wilkinson GR, McAllister CB, Wood AJJ. Increased toxicity and reduced clearance of lidocaine by cimetidine. Ann Intern Med 1982;96:572594. 8. Bussey HI. Update on the influence of quinidine and other agents on digitalis glycosides. Am Heart J 1984;107:143-146. 9. Salerno DM, Granrud G, Sharkey P, Asinger R, Hodges M. A controlled trial of propafenone for treatment of frequent and repetitive ventricular premature complexes. Am J Cardiol1984;53:77-83. 10. Moysey JO, Jaggarao NSV, Grundy EN, Chamberlain DA. Amiodarone increases plasma digoxin concentrations. Br Med J 1981;282:272. 11. Pederson KE, Dorph-Pedersen A, Hvidt S, Klitgaard NA, Nielsen-Kudsk F. Digoxin-verapamil interaction. Clin Pharmacol Ther 1981;30:311-316. 12. Oyama Y, Fujii S, Kanda K, Akino E, Kawasaki H, Nagata M, Goto K. Digoxin-diltiazem interaction. Am J Cardiol 1984;53:1480-1481. 13. MacFarland RT, Moeller VR, Pieniaszek HJ, Whitney CC, Marcus FI. Assessment of the potential pharmacokinetic interaction between digoxin and Ethmozine. J Clin Pharmacol1985;25:138-143, 14. Kennedy HL, Sprague MK, Redd RM, Wiens RD, Blum RI, Buckingham TA. Serum digoxin concentrations during Ethmozine antiarrhythmic therapy. Am Heart J, 1986;111:667-672.
Moricizine HCI, a phenothiazine derivative synthesized in the USSR in 1964, has been shown to be an orally effective antiarrhythmic drug. Moricizine HCI has demonstrated a low incidence of generally mild and transient side effects. Studies of possible drug interaction between it and other drugs most likely to be administered to cardiovascular patients are currently being conducted in US drug trials. Possible interactions between moricizine HCI and cimetidine, and between moricizine HCI and digoxin, are reviewed. The coadministration of moricizine HCI had no effect on the pharmacokinetics of cimetidine; in contrast, cimetidine administration slowed the
M
J. J. WOOD, MD, ChB, MS
elimination of moricizine HCI. The implications of greater therapeutic and/or toxic effects of moricizine HCI must be considered for patients receiving cimetidine and moricizine HCI concomitantly. No significant interactions were observed when monitoring serum levels of moricizine HCI and digoxin in patients with normal renal function receiving digoxin therapy for congestive heart failure or atrial fibrillation. Moricizine HCI in therapeutic dosages (10 mg/kg daily) demonstrated antiarrhythmic efficacy without significant alterations in serum digoxin levels. (Am J Cardiol 1987;60:79F-82F)
an elimination half-life ranging from 8 to 12 hours (mean 4.0).4 Moricizine HCI is extensively (95% to 97%) bound to human plasma proteins and undergoes a first-pass metabolism, where biotransformation is thought to be the predominant route of elimination4 Studies conducted with radiolabeled agents indicate that moricizine HCl has numerous metabolites (at least 18) that are excreted in both urine (4O%] and feces (60%).4Less than 1% of intact moricizine HCl is eliminated in urine or feces in humans4 Early data indicate that patients taking moricizine HCl tend to have higher normalized plasma levels, and that the elimination half-life is longer and more variable than in normal human subjects.4 Relatively few data exist with regard to the pharmacokinetics of moricizine HCl in cardiovascular patients.
oricizine HCl (Ethmozine@)*, a phenothiazine derivative synthesized in the USSR in 1964, has been shown to be an orally effective antiarrhythmic drug in both animals and humansY Moricizine HCl is currently undergoing investigational antiarrhythmic drug trials in the US; its electrophysiologic properties are similar to those of class IB and IC antiarrhythmic agents. Moricizine HCl has notably demonstrated a low incidence of side effects, which are generally mild to moderate in severity, transient and without serious toxicity.Z,3 Studies of possible drug interaction between moricizine HCl and other drugs most likely to be administered to cardiovascular patients (e.g., digoxin, cimetidine, warfarin, etc.] are in their infancy. We will review the early reports of effects of moricizine HCl when concomitant therapy of cimetidine and digoxin is administered.
Drug Interactions Cimetidine and moricizine HCI: The effect of moricizine HCl on cimetidine pharmacokinetics was studied by Biollaz et al5 in 8 normal volunteers 22 to 40 years of age [mean 27.6) who had received no medication for at least 10 days before the study. In the first
Pharmacokinetics Central to any discussion of a new drug with regard to drug interaction is a brief understanding of its normal pharmacokinetics. Studies performed in young human subjects have shown moricizine HCI to be well absorbed by the gastrointestinal tract, with mean peak plasma levels occurring between 0.7 and 1.5 hours and
From the Division of Cardiology, Department of Internal Medicine, St. Louis University Medical Center, St. Louis, Missouri, Address for reprints: Harold L. Kennedy, MD, MPH, Division of Cardiology, St. Louis University Medical Center, 1325 South Grant Boulevard, St. Louis, Missouri 63104.
* Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozinem. 79F
8OF
A SYMPOSIUM:
ETHMOZINEW (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
TABLE I Kinetics of Single Oral Dose of 500 mg Moricizine Alone and with Cimetidine Pretreatment Moricizine HCI AUC oto @J Cm hr/ml) Cl (mllminlkg) T% P (hr.9 Vd (liters/kg)
5.6 f 1.3
38.2 f
10.7
HCI
Moricizine HCI + Cimetidine 7.8 f
1.2”
19.7 f 4.2’
3.4 f 0.5
4.6 f 0.5”
11.1 f 3.1
8.2 f 1.2
AUC = area under the time-concentration curve; Cl = clearance; terminal half-life of elimination; Vd = apparent volume of distribution. Data are mean f standard error of the mean. * p <0.03 compared with before cimetidine administration,
T% =
phase, a single dose of 500 mg moricizine HCl was administered orally after an overnight fast. Blood samples for the measurement of drug levels were drawn immediately before drug administration and at periodic intervals up to 24 hours later. Blood pressure, pulse rate and standard electrocardiographic readings were recorded before and at regular intervals after drug administration. After a l-week washout period, the subjects entered the second phase of the study, in which they took cimetidine 300 mg 4 times daily for 1 week. After 7 days of cimetidine administration, plasma levels of cimetidine were determined during the 6hour dosing interval. While continuing cimetidine administration, a single dose of 500 mg moricizine HCl was again administered and blood samples were collected for the measurement of cimetidine and moricizine HCl. Blood pressure, heart rate and standard electrocardiographic readings were again recorded at the same times as in the first phase of the study. The coadministration of moricizine HCl had no effect on the pharmacokinetics of cimetidine, and the clearance of cimetidine was unchanged. In contrast, cimetidine administration significantly altered the elimination of moricizine HCl, as shown in Table I5 The plasma concentration of moricizine HCI was higher during cimetidine administration, resulting in an increase in the area under the curve and a decrease in clearance (Table I]. Cimetidine slowed the elimination of moricizine HCl, resulting in an increase of the latter agent’s half-life of elimination. Although moricizine HCl appeared to prolong both the PR and QRS intervals, there was no detectable increased prolongation of the PR interval when cimetidine and moricizine HCl were coadministered. Corrected QT intervals were not altered significantly by either moricizine HCl alone or the coadministration of moricizine HCl and cimetidine. Blood pressure and heart rate were unaltered during the trial.5 Thus, the study of Biollaz et al5 showed that moricizine HCl should be added to the list of drugs whose metabolism is inhibited by cimetidine. Previous reports have shown that cimetidine is a potent inhibitor
AGENT
of the metabolism of other antiarrhythmic agents, including propranolo16 and lidocainen7 Biollaz et al5 found that the mean clearance of moricizine HCl was halved when cimetidine was administered for 1 week and was accompanied by a marked increase in moricizine HCl plasma concentration. The subjects with the highest pre-cimetidine drug clearance had the greatest decrease in clearance during cimetidine treatment, indicating considerable interindividual variation. The clinical implications of these findings indicate that patients receiving cimetidine and moricizine HCl simultaneously, a likely combination in the intensive care unit, will have increased moricizine HCl plasma concentrations and potentially greater therapeutic and/or toxic effects. Digoxin and moricizine HCl: Several antiarrhythmic drugs, including quinidine,8 propafenone,g amiodarone,lO verapamilll and diltiazem,12 have been shown to alter serum digoxin levels. Clearly, studies of possible moricizine HCl-digoxin interaction are of current interest. MacFarland et all3 reported on 9 normal male adults between the ages of 22 and 28 years who were studied for moricizine HCl-digoxin interaction. On day 1, each subject received a 1.0 mg intravenous dose of digoxin, and periodic blood samples for digoxin determinations were drawn for the next 4 days. After a l&day washout period, subjects received oral moricizine HCl in a dosage of 12 mg/kg daily (4 mg/kg 3 times daily) for a 12-day period. Blood level determinations for moricizine HCl were then obtained, and subjects received a second 1.0 mg dose of intravenous digoxin immediately after taking their morning dose of moricizine HCl. Blood level determinations for moricizine HCl were again made, and blood and urine collections were made simultaneously for digoxin determinations. No differences were noted in serum digoxin concentrations compared with time curves in the presence of moricizine HCl compared with digoxin concentrations in the absence of moricizine HCl [Table II). Additionally there was no alteration in the profile of moricizine HCl plasma concentration versus time before and after administration of intravenous digoxin .13Therefore, the findings of MacFarland et al indicated that no pharmacokinetic interaction occurs when a single intravenous dose of digoxin is administered with multiple oral doses of moricizine HCl. We recently reported a study of 13 adult patients aged 19 to 72 years (mean 57) who received digoxin therapy for congestive heart failure or atria1 fibrillation as well as moricizine HCl antiarrhythmic therapy.14 All patients had non-life-threatening, hemodynamically stable ventricular arrhythmias, with a mean hourly frequency of 130 ventricular ectopic beats (VEBs), and normal serum creatinine levels. All patients had received oral digoxin as maintenance therapy for at least 14 consecutive days before the study, were deemed clinically stable and required antiarrhythmic therapy for suppression of VEBs. A singleblind, placebo-controlled protocol included 1 week of placebo administration, 2 weeks of moricizine HCl therapy and, after drug therapy, another 1 week of
October 16, 1987
TABLE II
Pharmacokinetics Elimination
THE AMERICAN
of Digoxin (D) in the Absence and Presence of Moricizine
Pt.
D
D+M
D
1 2 3 4 5 6 7 8 9 Mean f SD
37.4 50.2 50.5 52.1 45.3 49.1 49.3 39.1 42.9 45.6”
28.3 36.7 50.4 55.4 46.9 58.4 55.0 38.8 38.6 43.1”
11.70 15.60 14.50 9.20 9.17 7.70 8.22 11.00 14.80 11.3 f 3.01
9.60 12.70 12.50 8.93 9.10 15.80 9.45 11.40 12.40 11.3 f 2.28
0.0 (I)
*WEEK
l,r=0.90
WEEK2
.
r=0.88
l-T 00
0.5
SERUM
1.5 PLACEBO
1.0
DIGOXIN
DURING
20 (ng ml)
2.5
FIGUBE 1. Although mean serum digoxin concentrations tended to be slightly higher (10% to 15%) during moricizine HCI therapy, these differences were not statistically significant. Reproduced with permission from Am Heart J.14
TABLE Ill Mean Serum Digoxin and Moricirine Concentrations During Short-Term Study Pts. W Placebo Moricizine HCI, week 1 Moricizine HCI, week 2 Post-treatment placebo
13 13 13 7
Digoxin (w/ml) 0.91 1.13 1.06 0.83
f f f f
0.12 0.16 0.11 0.27
HCI
Moricizine Wml) 0.00 0.15 0.14 0.00
HCI
L!z0.00 f 0.03 f 0.03 f 0.00
Data are mean f standard error of the mean.
placebo administration. Each patient received a therapeutic dose of oral digoxin (9 patients 0.25 mg, 4 patients 0.125 mg) and moricizine HCl in an approximate dosage of 10 mg/kg daily (equally divided 3 times daily). At the end of each week of placebo, moricizine HCl and post-therapy placebo administrations, blood samples for serum digoxin and moricizine HCl determinations were obtained during oral digoxin administration on 2 consecutive days. Six patients, for medical and logistical reasons, did not enter the post-therapy
Volume 60
81F
HCI (M)
D
DtM
Cl, (ml/min/kg) D
DtM
3.61 3.59 3.31 2.04 2.34 1.81 1.93 3.24 3.98 2.87 f 0.837
* Harmonic mean. From Armitage P, Statistical Methods in Medical Research. Boston: Blackwell Cl = clearance; Cl,, = renal clearance; SD = standard deviation; Vz = volume of distribution. From reference 13 with permission.
^ E y 3.0 w 5- 25 1
OF CARDIOLOGY
Cl (ml/min/kg)
Vz (liters/kg)
Half-Life (hrs)
JOURNAL
3.92 3.99 2.86 1.86 2.24 3.12 1.99 3.40 3.72 3.01 zk 0.824 Scientific,
2.85 3.43 2.67 1.91 2.39 2.54 1.70 1.92 2.52 2.44 f 0.538
DtM 3.35 3.65 2.52 2.45 2.18 2.33 3.07 1.58 2.61 2.64 f 0.630
1971: 364-355.
placebo period. Twenty-four hour ambulatory electrocardiographic recordings for assessing ventricular arrhythmias were obtained on 2 consecutive days at the end of the placebo, treatment and post-treatment placebo periods, respectively.14 There was no significant difference (p >0.05) in serum digoxin or moricizine HCl levels between the placebo or post-treatment placebo and drug treatment periods (Table III]. There was a trend for slightly higher (10% to 15%) mean serum digoxin concentrations during moricizine HCl therapy (Table III). These differences, found during both weeks of moricizine HCI therapy, were neither statistically nor clinically significant. A close correlation of serum digoxin concentrations during the placebo period and during the first (r = 0.90)and second weeks (r = 0.88)of moricizine HCl therapy was noted (Fig. 1). Moricizine HCl concentrations were virtually unchanged during the 2 weeks of antiarrhythmic therapy (Table III]. Moreover, the efficacy of moricizine HCl therapy in suppressing ventricular ectopy during the first and second week of treatment was significant in these patients (Fig. 2). Therefore, serum digoxin concentrations during digoxin maintenance therapy in cardiac patients with normal renal function were found not to be clinically or statistically significantly affected during short-term moricizine HCl therapy. A cautionary note, however, is warranted in extending these observations to patients who may have impaired renal function. Early observations suggest that such patients may potentially manifest higher moricizine HCl levels, with possibly different consequences on serum digoxin levels.
Conclusions A significant interaction has been described between moricizine HCl and cimetidine in normal human subjects. The mean clearance of moricizine HCl was halved when cimetidine was administered 1 week before moricizine HCl; this resulted in a marked increase in moricizine HCl plasma concentration. No significant interactions were observed when monitoring serum levels of moricizine HCl and digoxin in patients with normal renal function receiving digoxin
82F
A SYMPOSIUM:
ETHMOZINE@ (MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
400 300 1 f 200: ‘\ 180-
L ,
11
did not result in either a clinically or statistically significant effect. Acknowledgment: We acknowledge the contributions of Frank I. Marcus, MD, to the patient data base.
References
160.
PLACEBO 142231 (13)
AGENT
WEEK 1 1426 (13)
WEEK 2 1317 (13)
POST-TREATMENT PLACEBO 125257 (7)
VEB:‘hr (NO. OF PATIENTS) FIGURE 2. Moricizine HCI was most effective in suppressing ventricular ectopic beats (VEB) during the 2 treatment weeks. Reproduced with permission from Am Heart J.14
therapy for congestive heart failure or atria1 fibrillation. Moricizine HCI in therapeutic dosages (10 mg/kg daily) demonstrated antiarrhythmic effectiveness without significant alterations of the serum digoxin level. There was a slight elevation (10% to 15%) of serum digoxin levels during 1 and 2 weeks of therapy, but this
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