Dose Effect of Moricizine on Suppression Ventricular Arrhythmias Joel Moiganroth,

To define the pharmacologic propertles of moricizine in patients with benign or potentially lethal ventricular arrhythmias, 1,072 patients in the moricizine data base through February 1987 were evaluated. In dose-ranging and titration trials as well as in a cross-study analysis of the entire data base, the minimally effective dose for moricizine was found to be 600 mglday and the optimal dose range from 600 to 900 mg/day. The dose efficacy relation plateaued beyond 900 mg/day. With use of a 75% reduction in ventricuiar premature complex frequency as the deflnition of a drug responder, 391 of 663 patients (67%) with paired Holter monitors demonstrated overall efficacy. The dose onset of moricizine was between 16 and 20 hours and the dose offset was at approximately 24 hwrs at the point when 60% of the ventricutar arrhythmia frequency returned to baseline. Although moricizinc was primarily given on a 3-times-aday regimen during clinical trials, dose interval evaluation suggested that a twice-a-day regimen may produce the same degree of efficacy although there are limited data regarding comparable safety. (Am J Cardiol1990;65:26D-31D)

From the Departments of Medicine & Cardiovascular Diseases, The Graduate Hospital and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Address for reprints: Joel Morganroth, MD, Center of Excellence for Cardiovascular Studies, The Graduate Hospital, One Graduate Plaza, Philadelphia, Pennsylvania 19146.

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of

MD

ntiarrhythmic drugs are prescribedby physicians to prevent or eliminate clinically important ventricular arrhythmias. ly2Becauseany therapeutic agent is potentially toxic, physicians should always seek the minimally effective dose required to reach the desired therapeutic end point. In addition, the proper dose interval of the therapeutic agent should be clearly established to eliminate any periods of inefficacy or potential adverse effects due to unnecessarily high peak drug concentration. During new drug development, careful clinical trials should be conducted to establish both dose-effect relations, onset of therapeutic action, offset of action and the proper interdose interval. This report describesthe data from the moricizine new drug application data basethat were usedto estab lish these important pharmacologic variables.

A

METHODS Study population: The moricizine new drug applica-

tion data base (as of February 1987) evaluated 1,072 people treated with moricizine for ventricular arrhythmias. This population consistedof 99 patients (9%) with benign, 576 (54%) with potentially lethal and 397 (37%) with lethal ventricular arrhythmias. * Concomitant cardiovascular agents were administered to 856 of 1,072 patients (80%). These included diuretic drugs in 535 (50%), vasodilators in 488 (46%), cardiac glycosidesin 445 (42%), calcium channel blockers in 183 (18%), p blockers in 175 (16%) and additional antiarrhythmic therapy in 131 ( 12%).Figure 1 displaysthe cardiovascular history of these 1,072 adults treated with moricizine for ventricular arrhythmias. Almost all of thesepatients had underlying cardiovasculardiseasewith over one-half having a history of myocardial infarction and only 7% having no structural cardiovasculardiseasewith ventricular arrhythmias, so-called idiopathic ventricular ectopic activity. Mythmia monitoring methods: To evaluate sup pressionof ventricular premature complexes(VPCs) or nonsustained ventricular tachycardia (VT), electrocardiographic monitoring (Holter monitoring) was performed. To qualify for inclusion in the dose-effectanalysis, patients had to have at least one 24-hour Holter monitor recording before institution of moricizine therapy, and at least one 24-hour Holter monitor recording with moricizine at a known dosage.A minimum of 18 of 24 hours of high quality electrocardiographic data was necessaryfor that Holter to be a qualified study. To qualify for entry and moricizine dosing, patients had to have at least 30 VPCs/hour on averageat baseline.The

CV HISTORY

- ADULTS

WITH VEA

Du Pont (n= 1072) % of Patients

100

with

CV Diseases

93%

90

FIGURE 1. The cardiovasadar (CV) historyoffheadultpaliedstrealedwifhmuricixinefurventrieular ectopic m (VW in fhe Du Ponf-sponsored data base is depicfed. CAD = colwmty amry disease; CHF=cmgedveheartfailwe;HT=hyperfenrion; MI = myocardial infarclicq Valv. = vahndar heart disease.

80 67%

70 60 50 40 30

17%

20

7%

10

I

1 CVD

CHF

MI

CAD

1

Type

effect of moricizine on the suppressionof VPCs was basedon the median or geometric mean percent change on moricizine comparedwith baseline.In addition, drug effect was evaluated as the percent of responderstaking moricizine. A responderwas defined as one who demonstrated at least a 75% reduction in mean VPCs per hour with moricizine at a particular dosecomparedwith baseline. A responderfor nonsustainedVT was defined when at least a 90% reduction in the number of beats in the form of nonsustainedVT occurred with moricizine compared with baseline. RESULTS

In interrogating the entire moricizine data base,583 patients had paired Holter monitoring for evaluation. The number of Holter recordingsper patient rangedfrom 2 to 54 (mean 13). Doseeffeei relations: The initial evaluation of morici-

HT

Valv.

Idiopathic VEA

of CVD

zine wasconductedin 2 separateprotocolsin hospitalized patients with benign or potentially lethal ventricular arrhythmias. The first trial included a j-center evaluation of moricizine (study numbers N5 through N9) in which 73 patients underwent therapy with a fixed daily moricizine doseof 300 to 900 mg/day given 3 times a day over 7 daysafter an initial 3 daysof placebobaselinemonitoring to establishentry criteria.3 The secondprotocol involved 2 sites(N39 and N47) in which 16patients weredosedwith moricizine from 900 to 1,650mg/day given 3 times a day for 10 days after a 2- to 3-day placebo baseline. These patients alsowere continuously monitored in the hospital. This single-blind placebo-controlled protocol demonstrated overall that median VPC frequency was reduced 66%in studiesN5 through N9 and 96%in N39 and N47 at the higher dosesof moricizine. Figure 2 shows the dose-response relation derived from the data from these2 typesof studies.The geometricmeanpercentreduction in

DOSE- RESPONSE FOR STUDIES N5-N9, N39 and N47 GEOMETRIC MEAN PERCENT REDUCTION FROM BASELINE vs DOSE Percent 100

Reduction

from Baseline

FlGURE2.lhedoseyiponseforthe ~+y~(~**~-

NS-NS,N3SandN47)bdf!picted

in

wwchthepevcsnf-franlbasehlelngeomemcmeanforpmmatumcomplexescomparedwnh moridimisdemonfhedailydlmeof sfraled.

80

60 Percent 50

I

55.2%

,

300

450

I 600

Reduction I 750

= [(l-lO[-0.058-O.O097(Dose)l) I 900

I 1050

I 1200

I 1350

I 1500

x 1001 I 1850

Daily Dose (mg)

THE AMERICAN JOURNAL OF CARDIOLOGY FEBRUARY 20,199O

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DOSE TITRATION Cumulative Cumulative

% of Patients

% Response

with,

(n=81)

75%1 in VPClHR

100 88% -I

90 7161

68% 60

3/5i

i3/60

78% -

80

FIGURE 3. The dose-titratia~~ respome framthetibdonstudyat5sitesN21 thRlt@hN?Shdcpicted-forSlptkldS.ACtlHhtb~mponre (-eanyf-f=d)forPatkmts whereachedatleasta75%rrductkn

13% -

52%

50 bildlW~ShOWll.TiWSt?dataSllOW

40

thatthedaii-optlmal6iese

30

rangeisfrom6OOtoSOOmg/day.

20 10 0

-

450

600

750 Daily Moricizine

Dose (mg)

1500

VPCs from baselineis comparedwith the daily fixed dose of moricizine. These data document a progressivedoseresponserelation for moriciiine and suggestthat doses less than 600 mg/day would be consideredsuboptimal with the minimally effective doseat 600 mg/day and the optimal range between 600 to 900 mg/day. In these 2 trials comprising a total of 89 patients, 23 patients received 300 to 450 mg/day and 17%were defined as responders.Among the 5 1 patients receiving 600 to 900 mg/day, 57%were declaredrespondersand in the 15 patients administered more than 900 mg/day, 73% were defined as responders. A formal dose titration study was conducted (study numbers N21 to N25) in 5 sites comprising 88 patients using a single-blind, placebo-baseline-controlledoutpatient design. After three 24-hour Holter monitoring sessions during a l-week placebo period, qualified patients were then given low, then medium, then high dosesof moricizine dependingon the VPC frequency response(48 hours of Holter monitoring) at the end of each week of dosing.Patients receiveda fixed doseof moricizine based TABLE I Cumulative Dose Effect Relation of Moricizine Cumulative Percent Responders Titration Daily Dose (mz)

Dose Response* (n = 89)

300 450 600 750 900 1,050 1.200 >1,200

4 10 49 74 85 90 93 98

l NSN9; N39 and N47. CAPS = Cardiac Arrhythmia tachycardia: VPCs = ventricular

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N21-N25 (n = 81)

CAPS (n = 98)

VPCS (n = 583)

NSVT (n = 332)

52 66 -

2 3 29 56 76 90 96 99

2 6 28 60 83 92 95 -

3 24 52 68 78 88 93

Entire Data Base

Suppression Trial; NSW = nonsustained premature complexes.

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N21-

N25

on body weight. Figure 3 details the cumulative percent responserate in this titration study and again documents the optimal doserange of 600 to 900 mg/day with little efficacy below 600 mg/day. &nnulative dose re!sponeeanalysis: A cross-study analysiswasperformedon the entire moricizine data base in 583 patients who had VPCs and at least one 24-hour Holter recording at baselineand one 24-hour Holter recording with moricizine therapy. Three hundred ninetyoneof these583 patients (67%) weredeclaredresponders, having met the criteria of at least a 75%reduction in VPC frequency with moricizine comparedwith baseline.After analyzing these data by carrying forward all patients as respondersreceiving higher doseswhether or not they receivedthat higher doseand carrying backward all nonrespondersto lower doseswhether or not they received that lower dose,Table I details the cumulative dose-effect relation. Thesedata for the entire data baseare compared with the initial doseresponse(N5 through N9, N39 and N47) and titration data (N21 through N25), as well as the Cardiac Arrhythmia Pilot Study, which was a parallel, placebo-controlledtrial in postmyocardial infarction patients who received 600 and 750 mg/day of moricizine.4The data again indicate that the optimal doserange for moricizine appearsto be between600 and 900 mg/ day, with little efficacy below 600 mg/day and with some increase in efficacy greater than 900 mg/day. In addition, an analysiswasconductedon 332 patients with nonsustainedVT in which the percent of patients respondingwas defined using at least a 90%reduction in nonsustainedVT frequency with the drug comparedwith baseline. Once again, the 600 to 900 mg/day schedule appears to be optimal. To evaluate the doseonset Deseensetef moricizine: of moricizine, patients with ventricular arrhythmias in the entire data base were extracted who had had a 24hour Holter recording on the first day of moricizine dosing. Becausethis was a retrospectiveanalysis, somepatients may not have had Holter monitoring data during

DOSE ONSET OF ACTIVITY (Nonresponders Median Percent

FIGURE4.ThedoseotmetofactMY~ Inaickbin~andrcrpondersatweok2(ateqmdsfisenewho mi&tedatioasta7S%fwtuc6minventttdarftrmatmcompkxcrperhour)is shownfsrpatkntswhshadHoltcrrecerdingsenthe6rstdayofmorkmedoring. Dosingwasona24bnem4daybasisat (0,8,16andihenagainat24hows).The cmsotef~ytimticac6vitY,demadarr atkasta7S%medanpercent~9 ocausafter16hours.

and Responders Day 1 Holters

Change from Mean Placebo

at Week 2)

Baseline

-40

-60 --------B-d -60

-100

I

I

I

I

I

0 4

2

4

6

t

Dosed

I

I

I

I

6 10 12 14 16 18 Hours After the First Dose

I

I

I

I,

20

22

24 b

t

the first few hours of moricizine therapy on day 1 of therapy and someHolter recordingsmay not have lasted a full 24 hours. Figure 4 details the data which demonstrate in nonrespondersand respondersat week2 of moricizine therapy that the onset of moricizine activity (as judged by the medium percent changein VPC frequency from baseline) appearsto occur between16 and 20 hours after initiation of therapy. Thus, when starting moricizine for patients with ventricular ectopic activity, one would not expect to seea significant suppressionof VPCs until at least the latter half of the first day of dosing. Doseoffwt of morieizine: To evaluate the doseoffset of moricizine, patients enrolled in the formal titration studies who had a Holter monitor placed immediately after discontinuation of moricizine that ran for at least 48 hours were retrospectively collected. Data were available

I

t

for this analysis from the titration studiesat centersN9, N39 and N47 and from center N41 which evaluatedthe dose interval for moricizine (see later). These inclusion criteria were met in 26 responders.Figure 5 shows the percentof baselineVPC frequency that wasreachedwith regard to the time after discontinuation of moricizine. More than 24 hours elapsedbefore at least 50%of baseline VPC frequency reoccurred Time interval for moricizine dosing: A single-blind placebo-controlledcrossoverstudy in 24 patients wasconducted at 2 centers (study numbers N41 and N45) in which patients after a l-week placebobaselineunderwent 48 hours of Holter monitoring to determine if at least 30 VPCs/hour were present.Qualifiers were randomized to receive a fmed doseof moricizine basedon body weight for 1 weekeither as 2- or 3-times-a-dayregimen.5After a

DOSE OFFSET OF ACTIVITY (26 Responders) FlGURE5.ThedoseoffsetofadMty ofmaidMeisdonmldratedin26rerpomkrr-~ww tdds(N9,N36andN47)aswe6asthe doseintorvaltrbldtoH41.Twenly-six WpOdOl%WMOfOWldWhOh8dd

kast48hewsofHstter~npafterrecshhgtheiriastdossofmorkixine.Thedesoatfsotqspears of-m-cxlmplexes(WCS) hove tv3tumd to the basehelreqmay.

Percent of Mean Placebo Baseline Hourly Total VPC Rate 130 120 110 100 90 80 70 60 50 40 30 20 10 o-

I I I I I I I I I I I I I I I I I I I I I I I I

0

2

4

6

6 1012141616202224262630323436364042444646

Hours After the Final Dose Last Dose

e NQ, N39, N41. N47 ,

THE AMERICAN JOURNAL OF CARDIOLOGY FEBRUARY 20.1990

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TOTAL VPC/HR Mean Total VPCs / HR

800

r

DURING STEADY STATE

B.I.D. = Middle Dose Group (750, 900 mg/day) . (n=9 Responders)

700 t

-

FlGURE6.lReSrarponderrhthe 6088illtSW8l(St&Sik?SR41MDd

0 Placebo Baseline 0 Moricizine Day 7

n

N46)whomceivednwMxineona bke-aday bash (BAD.) ware demonstmtedinwhMtotalvedic&rpreInahum complexes (VPCS) per how are PbRdagdllSttlWhOlU&VPCfraqK!lIcyformoridzhatday7ofther~Y-wHh~pboeboperiod. TIledata-thatintheeepathntethelwke-a4yregimsnwasnot cOfdatdwilhanybraakthrou&in VPC traqumey.

100 0 0am 4 Dose t

8Pm Time of Day (24 HR)

8am b

t

t

l-week washout, patients were crossedover to the alternate dosing regimen. Holter monitoring was obtained for at least 48 hours to judge therapeutic effect. Of the 24 patients who enteredthis trial, 17 completedthe 3-timesa-day dosingscheduleand 18 the 2-times-a-dayschedule. Overall, 71% of patients respondedon the 3-times-a-day vs 75%on the 2-times-a-day regimen. The mean percent of VPC reduction was90%for the 3-times-a-dayarm and 95% for the 2-times-a-day arm. Figure 6 details the hour-to-hour VPC frequency among the respondersin the optimal dose group compared with the placebo baseline. These data show that there was no evidenceof changein VPC frequency at the endof every 1Zhour dosinginterval, suggestingthat moricizine may be effective as a twice-a-day agent although most of the patients in the data basewere given a 3-timesa-day regimen. DISCUSSION Evaluation of the pharmacologic propertiesof antiarrhythmic drugs in patients with ventricular ectopicactivity requires establishmentof careful doseeffect relations. The data in this manuscript have describedthe optimal doserange, doseonset,doseoffset and dosing interval for moricizine in patients with benign or potentially lethal ventricular arrhythmias. Early doseranging, single-blind, placebo-controlled trials demonstratedthat the minimal effective dose of moricizine appears to be 600 mg/day with increasing efficacy as the dose is increased.3,6This increasing efficacy begins to plateau after 900 mg/day. Thus, the optimal doserange for moricizine appearsto be between600 and 900 mg/day. Although no formal parallel placebo-controlleddosing study was performed in this data base,a study designthat probably is the most effective way of demonstrating doseeffect relations,’ the data from the titration studies and the total data basecrossstudy analysis (Table I) were all confirmatory in estab-

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lishing 600 to 900 mg/day as the optimal doserange for moricizine. When these data were compared with data from The Cardiac Arrhythmia SuppressionTrial,4 a parallel placebo-controlled data base,the comparable dose range was demonstrated.Overall, the efficacy of moricizine in 583 patients with paired Holter monitoring data was 67%, which is quite comparable for quinidine in similar populations and more effective than classIB and II antiarrhythmic agents.8 The onset of moricizine’s antiarrhythmic action appears to be about 16 to 20 hours after initiating therapy on a 3-times-a-day basis. Becausemoricizine is highly metabolized in the liver to many metabolites, some of which are probably active, the full antiarrhythmic effect of this agent appearsto require this biotransformation.9 Similarly, the offset of effect of moricizine appears to occur after many hours to perhapsa day or more, again suggestingthat the active metabolites have a prolonged biologic half-life. In patients with symptomaticventricular arrhythmias requiring antiarrhythmic drug suppression,complianceis always an important issue.The data from the dose-interval trials suggest that moricizine is as effective when given twice a day or 3 times a day.5 This finding is consistent with the possibility of a prolonged biologic half-life for the active metabolites.More data are needed to evaluatethe relative safety of 2- vs 3-times-a-daymoricizine use,particularly sincemost of the safetydata in the moricizine data basewerederivedfrom the 3-times-a-day dosing schedule. The data describedin this manuscript cannot be necessarily extrapolated to patients with other forms of ventricular arrhythmias such as malignant ventricular tachyarrhythmias or to patients with supraventricular arrhythmias. Antiarrhythmic drugs must be evaluated separately in these populations becauseit is often found that lower dosesof the antiarrhythmic drug are necessary

to maintain a favorable efficacy vs safety balance,particularly in treating patients with more seriousventricular tachyarrhythmias.1° REFERENCES 1. Morganroth J. Premature ventricular complexes: diagnosis and indications for therapy. JAMA 1984;252:673-676. 2. Bigger JT. Identification of patients at high risk for sudden cardiac death. Am J Cardiol 1984;54:3D-8D. 3. Morganroth J, Pearlman AS, Kunkman WB, Horowitz LN, Iuephsa ME, Michelson EL. Ethmozine: a new antiarrhythmic agent developed in the USSR: efficacy and tolerance. Am Heart J 1979,98:621-628. 4. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the

lirst year after myocardial infarction: the CAPS. Am J Cardiol1988,61:501-509. I. Morganroth J. Safety and efficacy of a twice-daily dosing regimen for moricizinc (ethmoxine). Am Heart J 1985;110:1188-1192. 6. Podrid PT, Lyakishev A, Lawn B, Maxur N. Ethmoxine-a new antiarrhythmic drug for suppressing ventricular premature complexes. Circulation 1980; 61:450-457. 7. Morganroth J, Pool P, Miller R, Hsu P, Lee I, Clark DM for the Encainide Research Group. Dose-response range of en&tide for benign and potentially lethal ventricular arrhythmias. Am J Cardiol 1986;57:769-774. 3. Morganroth J. Ambulatory electrocardiographic monitoring in the evaluation of new antiarrhythmic drugs. Circulation 1986:73:suppl ll:ll-92-H-97. 9. Pieniasxek HJ. Disposition of orally administered 14Cethmoxine in healthy volunteers. Alpha Academy of Pharmaceutical Sciences. 1984;14:244. 10. Morganroth J, Anderson JL, Gentxkow, GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from llecainide. JACC I986:8:6076lS.

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