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Practical Optimisation of Antiarrhythmic Drug Therapy Using Pharmacokinetic Principles krry L. Baumall, J/aneke Dekker Schoen and Timofhy 1. Hoo" Departments of Pharmacy Pracllcc and I\kdlClnl'. Section of Cardlolog)'. l ' nl\('r.;II) of 11111'1015 al Chicago. Chicago. I lhnois. USA

Contents lSI

Summary

152

I. Uniqueness of AJ"l l larrh)lhmlcs l.I Variables $J)C("ilic 10 Ihe Arrhrlhnm

152

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158 158

m

162

S ummary

U Variables Spc(ific 10 Ihe Drug 2. lndl\' iduahsed Target Concentrations 2.1 Shorl Term Results 2.2 Long Trrm Rrsul\s 2.3 Limitations of Ihe Target Method 3. I0I113! Dosing DUring Drug Testing 3. 1 Strategies 3.2 Construction of a Nomogram 4. long Term Dosage Adjustment

The Opllffil!klllOn of antiarrhythmic drug Iherap~ IS dl."penden! on Ihe definllions and methods of shon lerm I."ffil."aq II."Sling and thl." characterISti cs of those drugs used for rhythm disturbances. Thc chOice of an Initial antiarrhythmic drug dosage IS highly empirical. and Will remain so until the mrasuremen t offret' concentrauons. enanuomeric fractions and genetic phenOl)'ping bccoml."S routine. Howenr. the clin iCian can drvlse an effiCient inllial dosage for I."mCacy tl."sting procl."dures based on phannaeokinetic principles and d isposi tion variables in the litrrature. In this regard. a nomogram for commonly used agents and dosage5 was consm,lctl."d and IS offered as a guide to accomplish Ihis goal. Venfication of the accuracy and usefulness of thiS no mogram In a proSpl.'("tl,'r manner In patients wllh symptomatic tachyarrh)'thmlas IS Silil required. On a long term baSIS. dosage regimens can Ix modifi«l by the use o f pharmacokinctic prinCiples and pallent· spe-cific target concentrations, in accordance lI.. ith the methods used to monitor arrhythmia 1"\"CUTTl"nce and drug-relat«l sidr effl."("ts.

Clinicians arc frequently called upon \0 select an effective dose for drugs which exhibit complex pharmacokinetics. For a number of drugs. the

method of choosing an initial dose and subse· quently tailoring long term therapy in order to meet therapeutic goals has been well investigated. For

'" 0eeI0e it patl&llt 1'11$ • tachycardia which should De treated. ChooM .ntlarrhythmlC drug Choose iI'Iitial dOse

()pI""'M .1lOr1 l8fm 'IIO'men Test IHICIOC)' 10 predICt long te"," Illect/Yenes,

Monotor lor IIde .fllletS and leeurrenee C\ptlmlse long ISfm regwnan

example. there exist several relatively simple. prac· tical and well tested nomograms that help the clinician select the appropriate dose of theophylline (Jusko CI al. 1977: Powell ct al. 1978). anlibiolics (Modlering e l 31. 1981; Sarrubi & Hull 1978) and anliconvulsanls(Ludden el 31. 1976: Richcns 1979: Veich et at 1981). These 100ls are deSIgned to assist Ihe user in selecting an effective initial dose for a specific palient without an unacceptable risk of serious toxicity. Orten. Ihe reSulting serum concen· tration becomes one of the end-points of treat· ment. This approach does not hold for antiarrhyth. mic drugs: no such l001s exist. Several unique characteristics of antiarrhythmic agents account for this fact and they have been reviewed previously (Latini et al. 1990; McCollam et al. 1989). The purpose of this review is to provide practical guidelines for choosing an initial dose of an oral antiarrhythmIc agent and optimising long term therapy using pharmacokinetic principlcs.

I. Uniqueness of Antiarrhythmics The steps involved in treating a given patient with a rhythm disturbance are listed in table I. Problcms encountered during this stepwise approach ca n be divided into those regarding the patient's arrhythmia and those specific to the antiarrhythmic drug. 1. 1 Variables Specific to the Arrhythmia The ultimate goals in antiarrhythmic drug therapy are to prevent troublesome or serious symptoms of the tachycardia. and to prolong life .

Clm PharmaroJ..lrlt1 . 20 (!) IWI

These are often nebulous goals In that clinicians typically predict long term effective therap) by evaluating surrogate markers ofshon term drug efficacy. The treatment of premature ventricular beats with antiarrhythmics provides an example of the problems inhcrent In this type of approach . Man) physiCians have traditionally used antiarrhythmics to suppress compkx ventricular ectOpy (often asymptomatic) in patients with heart disease because these markers were harbingers of premature death (Ruberman et al. 1977; Vlay 1985). Suppression of the marker during short term therapy was presumed to predict long term effectiveness by preventing more senous ventricular arrhythmias. This practice is now discouraged because of the results of the Cardiac Arrh ythmia Suppression Trial (CAST) which showed that type Ie antiarrhythmics actually increase the risk of death or cardiac arrest in patients after a myocardial infarction, despitc effective suppression of ventricular ectopy (CAST Investigators 1989). In addition to the important specific findings of the CAST, these results demonstrate that short term markers may not always reliably predict achievement of long term therapeutic goals. Continuous electrocardiographic (Holter) monitoring and clcctrophysiological drug testing by invasive programmed stimulation are the currently accepted methods used to predict the long term effeetiveness of antiarrhythmic drug therapy, Although objective in nature, there are problems with both of these methods regarding the goals of drug efficacy. Because recurrent symptomatic tach ycardias tend to be highly sporadic (Morgan roth et al. 1978; Winkle 1978). suppression of the arrhythmia as shown by serial Holter monitor tracings are of modest value unless the episodes recur very frequently (e.g. I to 2 per day). Electrophysiological drug testing in these cases usually provides a more definitive answer. drug response in the laboratory has been shown to predict long term effectiveness in 80 to 90% of cases (Mason & Winkk 1980; Mitchell et a\. 1987; Platia & Reed 1986). However, the cri teria used to evaluate drug response may vary from centre to centre. Most agree that in a patient with an inducible sustained

Practical US( of Anllarrhylhmlc Pharmacokmellcs

tachycardia in the drug-free state. inability to induce the arrhythm ia. or induction of brief, self-termi nati ng, asymptomatic episodes. indicates a good predictive respo nse fo r effcrtive long term thera py (Swerdlow et a1. 1983). Others use the induc tion of a tachycardia by a mo re aggressive mode of stimulation or mductlOn of a slower. better tolerated tachycardia as an acceptable end.pomt. but the predlc1l\ e nature of these findmgs requires further study. SlImulallon and drug-testing protocols also vary considerably from laboratory to laboratory. Some clinical electrophysiologists tes t nea rly all available antiarrhythmic age nts in seq uential fas hion. whereas others use an abbreviated protocol with only I or 2 drugs. It does not appear to be possible to accurately predict which of the antiarrhythmic drugs Will be effcrtive solely from the characterIStiCS of the patient or the tachycardia (Swi ryn et a1. 1982). It may be possible. however. to shorten tcsting protocols dependen t on concordant reo sponses between similar drugs (Waxman et al. 1983). Despite these differences. optimisation of ini tial antiarrhythmic d rug therapy requ ires an objective and predictive account of efficacy. 1.2 Variables Speeific to the Drug

Anuarrhythmics are an extremely heterogeneous group of drugs in regard to their complex pharmacokinetics. Nearly all are metabolised to compounds with considerable antiarrhythm ic activity (Woosle)' & Roden 1983). and in some cases the active metabolites have different electrophysiological effects from the parent drug (Roden et a1. 1980). Also. man} newer. synthesised compounds are markNcd as racemic mixtures of 2 enantiomenc fractions. These cnanllomcrs may vary m their disposition and pharmacological aCIJ\I1) in a cllmcall) Significant manner (Hoon et al. 1986: Lima et al. 1985). Further. some drugs are highly bound to plasma proteinS and the degree of bind· 109 may considerably alter the antiarrhythmic ef· feet (Meffin et al. 1979: Rou tledge CI al. 1980). Other an tiarrhythmics undergo polymorphic me· tabolism as determmed by genetic phenotype (Sid-

'" dowayel al. 1987: Winkle et al. 198 1). As a resul t, these age nts act as partial prodrugs to active me· tabol ites in some patients. while other patients reiy primari ly on the parent compound for efficacy. All of these factors complicate t he development of effcrlive long lerm drug regi mens. With the exceplJon of prophylactic lidocaine (lignocaine) In the seuing of acute myocardial in· farction (Lie et al. 1974). antiarrhythmic drug con· centratlons alone do not provide an effective ther· apeutic end· point. The interpretation of a serum concentratio n of an an tiarrhythmic drug wit hin the con text of the accepled 't herapeutic ra nge' deserves fu rt her comment. We suspect that because seru m concentrations for these age nts are commonly avai lable on a commercial basis. these tests are often used 10 make dosage adjustment decisio ns. That IS. If t he concentration m a specific pauent IS retatively low or high. the dose may be increased or dcrreased in order to achieve a concentration within the published therapeutic range, sometimes withou t full conside ration of IOx ici!y or efficacy. The concept of a the rapeutic window docs give the elin ician a reasonable chance of achieving effcrtiveness without dose-related side effects ac ross a population of pa tients (Koch.Weser & Klein 1971). Ho .....ever, for antiarrhythmic agents it is at best a rough guide to dosing.. with limited utility in a specific patient. This is true for several rea· sons. First, effcrtive concentrations for some of the antiarrhythmics are extremely variable and unpre· dictable (see below). It may be ques tioned whether efficacy is dependent on the drug but not the con· centration: however. the re is some evidence thai response does rely on reaching a critical concen· tration (Greenspan el al. 1980: Horowitz el at. 1978) [fig. I J. In other words. there appears to be a 'threshold' for effcrt 10 a specific patient. Although not proven. 1\ is also possible that a patien! may pass through an effective range as the dose of the drug IS esealated. AbolitIOn of a re-entrant circuit by an anuarrhythmlc drug is a dynamic process that reqUIres a cntical balance of refractori ness and condUCllon velocity. It may be thaI at low concen· trations a drug preven ts re-entry but at higher con· centrations the resultant elcrtrophysiological effeet

C/m. PharmacokjrU'l. 10 (2) 1991

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fig. 1. Dose·rnponsc rela tionships of procainamide in induction of ven tricular tachycardia in a pIllient with recurrent sus-

tained ventricular tachycard ia; ( alsustained ventricular tachycardia induced during con trol; (b)slower venlrkular tachycardi a induced al a plasma procainamide concentra tion of 8.4 mill ; (e) again I slower ventricular tachycardia induced al a con· centration of 15.6 mill; (' ) sh ows thai ventricular tachycardia was nOI IndUCible al a concentration of 30.8 mg/L. This drug testing procedure sU~SIS that. in a specific patient, there is a hmhold I concentration for effect iveness (from Greenspan el al. 1980. wi th permission),

allows the substrate to again become viable. Sec· o ndly, commercially available assays measure total bound and unbound drug, including both enan· tiomers. As a result, the concentration that the

clinician must interpret represents a stew of free· active drug, bound·inactive drug, primary acti ve enantiomers and less active enantiomers. It is easy to appreciate how a concentration...effect relation·

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Pracllcal U§C: of Antlarrh)thmlc PharmacokmetiCS

shIp mOl) be difficull (0 establtsh on the basis of total drug concenlratlons. Lastly. because there has becn a relative plethora of new antiarrhythmics reccntly released or In clinical trials. few data regarding effectIve concentrations and concentration-cffect relationships of these agents are a\allablc. Although population-based therapeutIc ranges are of 1m Ie use In determining efficacy in an Indl\ Idual patIent. the) can somellmes be of \alue In a\oldlng dose-related toxiCllY. For example. dose-cscal:lIlon With disopyramlde that results In concentfallons higher than 5.0 mg/L is likely to result In anticholinergic toxicity. and mexiletine conccntratlOns grealcr than 2.0 mg/L will oncn resuI! In neurological toxiCllY. Although dose-related. man) (OXICllleS are readily dIscernible wllhOUI knowledge of the actual concentrauon. Conversely. some toxlCl\leS bear lillie or no relationshIp 10 concentration or dose: notably. the nsk of proarrhythmia cannot be predicted b~ serum concentrations. e.g. torsades de pointes due to quinidine seems to occur at low to 'therapeutic' concentrations (Bauman el a1. 1984).

2. Indi)'iduaJised Target Concentrations 2.1 Shon Term Results In an allempt to reconCIle some of the difficullies wllh dOSing anllarrh}thmic agents. the present authof"5 ha\e approached the problem b) uSing a pallent-speclfic 'target' concentratIOn. The pnncipies Inherent In this approach were ongmally suggested and studIed by Horowllz et a1. (1978) In a scrles of 1Ovestlgatlons aimed at determin10g the value of scnal elc-ctrophysiological studIes 10 predlcl10g drug response (pnmarily proca1Oamlde). To funher stud} 1Odn'lduahsed drug regImens. we anal}sed the concentratIOns of QUlnld1Oe. proca1OamIde and dlsop~ramide determined dunng an obJcc\l\e measurement of efficacy (i.c. inVaSIVe clec· trophyslologlcal drug tesling b) programmed stImulatIon) In L!3 patIents WIth symptomalic tachycardIas (BelT) el 011. 1988). The resulting concentrat ions were stratified into those drawn from responders and those from non responders. Re-

sponse to a specific drug was defined as Ihe inability to replicate Ihe tachycardia during drug therapy or induction of brief «15 beats). selfterminating arrhythmias. The results confirmed our suspicion that effective concentrations fo r these agents arc extremely variable: response was demonstrated In pallen IS with serum concentrations of Quinidine from 1.0 to 9.1 (mean:!: SO: 3.1 :!: 1.7) mg/L: proca1Oamlde 2.9 to 22.2 (7.4 :!: 4.0) mg/L: and disop)ramlde 3.6 to 7.5 (5.5 :!: 1.1) mg/L (fig. 2). The concentratIons 10 patients who wert nonresponders displayed a SImilar pattern of variability. and the mean 'ineffcctive' concentrations were not significantly differcnt from mean effective values. When the data were analysed separatcly fo r patients with re-cntrant paroxysmal supravcntricular tachycardIas and recurrent ventncular tachycardia. the results were nearly identical. Therefore. II seems ImpoSSIble to differentiate responders from non responders on the basis of drug concentration in patients wllh symptomatic arrhythmias. ThIS findlOg IS 10 contrast 10 other clinical situations where proper drug concentrations represent a major determi nant for response within a population o f patients. It docs not obviate. however. the presence or absence of a paticnt- and tachycardia-specific threshold concentration for anl1arrhythmic drugs. 2.2 Long Term Results AS the next step, 19 patients with sustamed symptomatic tachycardias who demonstrated efficacy as Judged by programmed stimulallon were followed on a long term basis (McCollam et a1. 1989). These palientS had antiarrhythmic drug concentral1ons determ10ed al the lime of electrophysiolOgical study and subsequently were dischargcd from the hospItal on the agent shown 10 be effeCd alph~·I·a""J r,l)·WI''';''~1I1 and IodO("alne dllpo .. 1I0n In myocardIal Infarrllon , Annals of Inlernal MedICIne 93: 701-704. 1980 Ruberman W. WClnblall E. Goldbell JD. Frank CWo ShapirO S Ventricular premalure bealS and monall1y afler myocardial Infarcllon. Ne ...' England Journal of MedlC1IlC 297: 7SG-751. 1917 Sarrubl FA. Hull J H. Amlkacln 5I:rum concc:nl",lIon$: preC to class I anllarrhylhmlc dru,s dunng tlcclroph~'$lotogtc sludy of 'Cnmcular IIch)'cardla Ame"':lIn Hean Journal 104: 43-SO. 1982 Via) SC Ho'" Ihe un1\"en.u) cardlolQ&lst l",alS "tnITlcular P"'malUre bealS: a natlon""lde SU"·C) of 65 un,,'enlty medIcal centen. Amcnc;!n Hean Journal 110: 904·911. 1985 Voleh S. MUir KT. Shclner LB. Follalh F. 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164

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IleTptnmd RH. Wanl T. Roden OM. Avant GR. SUlIon WW, C\ a1. EnClillnidc dispOSliion ,n patients wilh chronic ClrrhO$IS. Oinical PharmacolOlY and Thcrapo:u\ics 4(); 14&-1 S