Review Article
Clinical Pharmacokinetics 14: 141-147 (1988) 0312-5963/88/0003-0141/$03.50/0 © ADIS Press Limited All rights reserved.
Clinical Pharmacokinetics of Encainide Dan M. Roden and Raymond L. Woosley Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville
Contents
Summary ...................................................................................................................................... 141 I. Encainide Disposition in Healthy Subjects ........................................................................... 142 2. Impact of Disease States or Concomitant Drug Therapy on Encainide Disposition ....... 144 3. Doses and Concentrations Associated with Efficacy and Toxicity ..................................... 145 4. Conclusion ............................................................................................................................... 146
Summary
The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methOxy-Odesmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide. and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers. who make up to 7% of the population. a first-pass effect is absent. encainide clearance is lower. and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers. plasma concentrations of active metabolites are low or undetectable. and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers. the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease. but no major dosage changes are required. On the other hand. excretion of encainide and its metabolites is impaired in individuals with renal disease. and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore. the dosage should be increased no more often than every 3 to 5 days. Intensive study of the pharmacokinetics of encainide has enhanced the understanding of pharmacogenetics and of the structure-activity relations of antiarrhythmic agents; however. because dose-concentration relations are so variable. routine plasma concentration monitoring will probably be of limited value in the care of patients receiving this agent.
Clinical Pharmacokinetics of Encainide
142
The antiarrhythmic agent encainide appears unique among drugs of its type in that active metabolites are responsible for the effects seen in most patients (Carey et a1. 1984; Gillis & Kates 1984; Winkle et a1. 1983). However, despite considerable interindividual variability in plasma concentrations of parent drug and metabolites achieved during therapy, remarkably little variability exists in dosages required to achieve arrhythmia suppression (Quart et a1. 1986b). Hence, although intensive study of encainide metabolism has increased knowledge in fields such as pharmacogenetics and structure-activity relations, routine monitoring of plasma concentrations of encainide or its metabolites during long term therapy is unlikely to be of great value, except in following compliance.
1. Encainide Disposition in Healthy Subjects In approximately 7% of healthy Caucasians and Blacks encainide does not undergo rapid biotransformation, due to the absence of the hepatic enzyme cytochrome P450db• This defect, which is heritable, is now recognised as responsible for the polymorphic metabolism of over two dozen drugs, including the antihypertensive drug debrisoquine (Woosley et a1. 1986), the !3-blocking agents me-
toprolol and bufurolol (Smith 1985), and the antiarrhythmic agent propafenone (Siddoway et a1. 1987). Encainide is highly water soluble, weakly basic (pKa = 10.2) and well absorbed following oral administration. The drug and its metabolites are generally assayed by a high performance liquid chromatography procedure (Majol & Gammans 1981). In extensive metabolisers (93% of patients) systemic availability is only 30 ± 7% (table I) because of first-pass hepatic metabolism (Wang et a1. 1984). The major metabolites are O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE), plasma concentrations of which are usually higher during long term therapy than those of encainide. When encainide therapy in extensive metabolisers is temporarily discontinued (fig. 1) plasma concentrations of encainide fall rapidly, with an elimination half-life of 2 to' 4 hours, while ODE and MODE persist, with apparent elimination half-lives of 4 to 8 hours and 12 to 20 hours, respectively. As described below, ODE and MODE are at least as potent as encainide; thus, a pharmacological effect of encainide therapy, such as arrhythmia suppression or QRS prolongation, may persist long after encainide itself is undetectable in plasma (Carey et a1. 1984; Winkle et a1. 1983).
Table I. Effects of the poor metaboliser phenotype, renal disease, and hepatic disease on the disposition of encainide and its metabolites. All data are presented after 2 days of treatment with encainide 50mg every 8 hours, except in patients with renal disease who received only 25mg every 8 hours for 2 days. Mean values ± SE Healthy subjects
Plasma encainide (#gIL) Plasma ODE (#gIL) Plasma MODE (#gIL) Plasma NDE (#gIL) Systemic bioavailability (%) Encainide t'h (h) Plasma protein binding (%) Oral clearance (L/min) SystemiC clearance (L/min) Vd ss (L)
EM
PM
18 ± 6 115 ± 11 94 ± 10 < 10 30 ± 7 2.3 ± 0.3 70 ± 2 11.7 ± 4.3 1.9 ± 0.2 265 ± 24
450 12 none 80 83-88 11.3 ± 0.3 78 ± 0.6 0.22 ± 0.3 0.18 ± 0.02
Renal disease
Hepatic disease EM
PM; n = 1
30 ± 5 207 ± 40 252 ± 80
63 ± 9 87 ± 18 113 ± 81
47 ± 6 1.6 ± 0.1 81 ± 1 3.6 ± 0.5 1.5 ± 0.1 205 ± 12
78 ± 19 3.6 ± 0.5
100 13.8
1.7 ± 0.2 1.2 ± 0.2 347 ± 82
0.27 0:3
Abbreviations: EM = extenSive metaboliser phenotype; PM = poor metaboliser phenotype; ODE MODE = 3-methoxy O-desmethyl encainide; NDE = N-desmethyl encainide; t'k = elimination half-life.
=
O-desmethyl encainide;
143
Clinical Pharmacokinetics of Encainide
--
:::J 01 ~
c: 0
~
300 200
E Q) 0
c: 0 0
100
m
E
Ul
m
a::
50
12
24
36
48
Time after last oral dose (h)
Fig. 1. Plasma concentrations of encainide (0) and its 2 major active metabolites, ODE (e) and MODE (0), in an extensive metaboliser patient receiving 35mg encainide every 8 hours. A final dose was given at time O. Ventricular ectopic depolarisations (VEDs) returned to their baseline value 9 hours later; note that encainide plasma concentrations were below the lower limit of assay sensitivity at that time «10 pg/L).
In 'poor metabolisers' encainide does not undergo significant pre-systemic hepatic metabolism (Wang et al. 1984); systemic clearance is much lower than in extensive metabolisers (0.18 ± 0.02 L/min vs 1.9 ± 0.2 L/min, respectively) and systemic availability approaches 100% (table I). ODE, if present, is detectable only at low plasma concentrations, MODE is generally absent, and low concentrations of a third metabolite, N-desmethyl encainide (NDE), may be present (fig. 2). Encainide itself is cleared much more slowly in poor metabolisers than in extensive metabolisers, with an elimination half-life of 8 to 12 hours. Thus, the parent drug accumulates with the result that pharmacological effects, such as arrhythmia suppression and QRS prolongation, are seen (Carey et al. 1984). In in vitro test systems (Elharrar & Zipes 1982), animal models (Dawson et al. 1984; Duff et al.
1983; Roden et al. 1982, 1984) and most recently patients (Barbey et aI. 1985), both ODE and MODE have been shown to produce pharmacological effects similar to those seen during encainide therapy, including arrhythmia suppression and QRS prolongation. Interestingly, encainide, ODE and MODE produce qualitatively different electrophysiological changes. In most studies, ODE is a more potent depressor of sodium channels and cardiac conduction (evidenced in patients by QRS widening) than either encainide or MODE (Carey et al. 1984; Fain et al. 1986). However, MODE is more potent than encainide or ODE in prolonging ventricular refractoriness in dogs (Fain et al. 1986) and QT interval in humans (Barbey et al. 1986), and unlike encainide and ODE, does not raise energy requirements for defibrillation in dogs (Fain et al. 1986). In studies in patients with ventricular arrhyth-
Clinical Pharmacokinetics of Encainide
N
I
I
o
CHs
144
1
I; HN'~~ ~OCHs Encalnlde
to 39.3 ± 5.6% in poor metabolisers (Wang et al. 1984). In contrast, recovery of ODE (10.6 ± 3.0% vs 3.0 ± 0.2%) and MODE (3.6 ± 2.7% vs none detected) was greater in extensive metabolisers. Studies using isotopically labelled drug in healthy volunteers have identified over 95% of the metabolic products of encainide (Blair et al. 1986); apart from ODE, MODE and NDE, most appear to be sulphate or glucuronide conjugates and are therefore unlikely to contribute to the pharmacological effects seen during long term encainide therapy.
2. Impact of Dilease Statu or Concomitant Drug Therapy on Encainide Dilpolition
OH
N""C'I O II
I
H
/. OCHs
NDE
N
o II
I
CHs
N ....CI U OCHs I H ....: OH MODE
Fig. 2. Pathways of encainide metabolism. The heavy arrows indicate cytochrome P450db-dependent biotransformations which occur in most patients (extensive metabolisers).
mias, MODE was detectable soon after intravenous ODE, but only in extensive metabolisers (Barbey et al. 1986). Hence, not only encainide 0demethylation but also ODE 3-methoxylation appears dependent on the presence of P450db (fig. 2). This 'double dependence' of MODE generation on P450db may explain its absence in poor metabolisers. Encainide and its metabolites are excreted renally, and the extent of urinary recovery is a function of metaboliser phenotype. In extensive metabolisers 4.9 ± 2.3% of an intravenous radiolabelled dose was recovered in the urine, compared
Although biotransformation of encainide occurs in the liver, liver disease itself has strikingly little effect on apparent encainide dose requirements. In a group of 6 patients with advanced cirrhosis and presumed to have the extensive metaboliser phenotype (Bergstrand et al. 1986a), encainide oral clearance was lower than in 8 healthy extensive metabolisers (1.7 ± 0.2 vs 11.7 ± 4.3 L/min), and systemic availability was more than 2 times greater (78 ± 17%). Mean plasma concentrations of ODE and MODE were similar, while those of the parent drug were slightly higher compared to data in healthy volunteer extensive metabolisers. With QRS prolongation as the index of pharmacological effect, no difference was detected between normal individuals and subjects with hepatic disease given the same encainide dosages (50mg every 8 hours). On the other hand, major encainide dose adjustments are required in patients with renal disease. Areas under the plasma concentration-time curves of encainide, ODE and MODE were 1.5 to 2.7 times higher in a group of 7 patients with advanced renal failure after a single 50mg dose of encainide than in 8 normal subjects (Bergstrand et al. 1986b). Subjects with renal disease subsequently received 25mg encainide every 8 hours (vs 50mg every 8 hours in normal subjects). Despite this dose adjustment, QRS duration was equally prolonged in both groups. Interestingly, encainide elimination half-life in the subjects with renal dis-
Clinical Pharmacokinetics of Encainide
ease was actually shorter than that seen in healthy individuals, despite their lower clearance. This difference was attributed to altered protein binding with resultant decreased volume of distribution. These studies of the impact of disease states on the disposition of encainide used only subjects with the apparent extensive metaboliser trait. In one subject with the poor metaboliser phenotype and advanced cirrhosis, encainide disposition was similar to that in healthy subjects with the poor metaboliser phenotype (Quart et al. 1986a). The metabolic fate of encainide in the rare patient with the poor metaboliser trait and advanced renal disease is unknown. Cimetidine, a potent blocker of hepatic metabolism, was studied in 13 subjects receiving 25mg encainide every 8 hours. Mean plasma concentrations of encainide, ODE and MODE all rose 32 to 43%. The mechanism(s) and clinical consequences of this interaction are unknown, but exaggerated encainide effect might be anticipated (Quart et al. 1986a). Digoxin can slow conduction in the atrioventricular node, but no additive toxicity has been observed when digoxin and encainide are combined. Average steady-state concentrations of digoxin were not altered significantly, e.g. 1.05 ± 0.14 ~g/L with placebo vs 1.03 ± 0.11 ~g/L with encainide 25mg four times a day in 17 cases (Quart 1986a). The pharmacokinetic consequences of combining encainide with amiodarone, another potent inhibitor of drug metabolism, are unknown. However, the use of encainide in combination with other cardioactive drugs should be approached with caution because of the theoretical risk of additive effects on conduction slowing. Interestingly, preliminary studies in our centre indicate a potential additive antiarrhythmic effect of encainide plus lignocaine (lidocaine) with no apparent change in disposition of either drug during combination therapy (Lineberry et al. 1987). Drugs such as phenytoin, rifampicin (rifampin), and phenobarbitone, which induce hepatic metabolism, do not appear at this time to exert a major effect on encainide metabolism. Although encainide, ODE, and MODE are 80 to 90% bound to plasma proteins, no displacement interactions are
145
known or anticipated based on in vitro studies with the cardioactive drugs (digoxin, verapamil, lignocaine, propranolol, desmethylimipramine, chlorpromazine, diazepam, and warfarin) [Quart et al. 1986a]. The specific protein fraction to which these agents are bound (albumin vs ai-acid glycoprotein) is unknown. In one study, food increased the mean time of maximum metabolite concentration (ODE from 1.3 to 2.3 hours; MODE from 2.3 to 3.1 hours), while producing no change in area under the curve after a single 50mg dose of encainide (unpublished data on file; Bristol Myers). Thus, food may delay encainide absorption but probably does not alter the extent of its biotransformation to active metabolites.
3. Doses and Concentrations Associated with Efficacy and Toxicity The assumption underlying the clinical strategy of therapeutic drug monitoring is that there exists a reasonable correlation between a range of plasma concentrations associated with a desired drug effect and a range of plasma concentrations associated with unwanted drug effects. For encainide, studies in patients have suggested that concentrations of 250 ~gjL (encainide; achieved only after intravenous doses or in poor metabolisers), 30 ~gjL (ODE), and 100 ~g/L (MODE) are associated with an antiarrhythmic effect (Anderson et al. 1982; Barbey et al. 1986; Carey et al. 1984). Many fewer data are available to indicate an appropriate upper limit on plasma concentrations. In one study, a plasma ODE concentration above 307 ~gjL was associated with a higher risk of adverse effects, including aggravation of arrhythmias, during encainide therapy (Chesnie et al. 1983). However, !is indicated below, patients with certain types of heart disease appear to be at particular risk for cardiac side effects; in individuals with near-normal hearts who receive encainide, ODE concentrations well above 500 ~gj L can be recorded and appear well tolerated. Unfortunately, it is not possible to control plasma concentrations of either parent drug or metabolites during long term therapy. In one study
Clinical Pharmacokinetics of Encainide
(Barbey et al. 1986), mean plasma concentration of encainide in patients with the extensive metaboliser phenotype during effective therapy for nonsustained ventricular arrhythmias was 81 ± 57 p,g/ L (range 14 to 192 p,g/L). In this group, mean ODE was 189 ± 100 p,g/L (range 63 to 381 p,gfL) and mean MODE 142 ± 93 p,gfL (range 16 to 291 p,g/ L). In poor metabolisers plasma concentrations of encainide are generally in the 250 to 500 p,gfL range, with only very low concentrations of metabolites detected (Carey et al. 1982; Wang et al. 1984). The concept that antiarrhythmic drugs act by binding to a specific receptor on or near cardiac ionic channels also raises the possibility that parent drug and metabolites (of encainide or any other agent) may compete for access to such receptors (Bennett et al. 1986). Thus, in view of potential binding interactions, the differing pharmacological effects of encainide and its metabolites (in particular MODE), and the varying potencies of these substances, it does not appear likely that the plasma concentration monitoring strategy which is frequently adopted for other antiarrhythmic drugs will be successfully applied to encainide. In fact, analysis of a large encainide database showed that the dosages required to produce a desired pharmacological effect (arrhythmia suppression) were no different between extensive and poor metabolisers (Quart et al. 1986b). Moreover, the incidence of adverse reactions (both mild and severe) was similar in the two groups. Hence, as with any other antiarrhythmic agent, the starting dosages of encainide should be low and increased only if, after accumulation to steady-state of both parent drug and metabolites, a desired pharmacological effect is not seen (Antonaccio & VeIjee 1986). Dosages above 200 mg/day have been associated with a higher incidence of minor and serious side effects (including arrhythmia aggravation) in both extensive and poor metabolisers. In practice, this generally means starting dosages of 25mg 8 hourly (25mg once daily in patients with severe renal disease). In extensive metabolisers ODE and MODE accumulate to stead~-state in 3 to 5 days, while in poor metab9lisers encainide itself will accumulate to steady-state in this period
146
of time. Thus, if after 3 to 5 days on encainide 25mg 8 hourly, adverse effects are absent and no desired effect is seen, the dose may be cautiously increased. QRS widening is a common finding during encainide therapy and may serve as an indicator of the presence of a pharmacological effect. Dosages above 200 mg/day and/or marked QRS widening (over 30%) may be tolerated in some subjects, but carry a risk of aggravation of arrhythmias, particularly in certain patient subgroups such as those with sustained ventricular tachycardia secondary to remote myocardial infarction and aneurysm formation.
4. Conclusion The intensive study of the factors responsible for interindividual variability in plasma encainide concentrations has contributed greatly to an increased understanding of genetic factors in drug metabolism and the possible relationship between chemical structure and pharmacological effects in this sub-class of agents. From a practical point of view, however, the interindividual variability seen in plasma concentrations of encainide and its metabolites suggests that plasma concentration monitoring will be of limited value, while observation of the electrocardiogram may be a better guide to encainide dosing. Clinical pharmacokinetic information strongly suggests that dose increases be made no more often than every 3 to 5 days, and that particularly small starting dosages should be used in patients with advanced renal disease. Encainide is a potent drug which, if used with a clear understanding of these pharmacokinetic and pharmacodynamic principles, can result in effective therapy for many patients with cardiac arrhythmias.
Acknowledgement This study was supported in part by grants from the United Public Health Service (GM31304 and HL36724).
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Clinical Pharmacokinetics of Encainide
Antonaccio MJ, Verjee S. Dosing recommendations for encainide. American Journal of Cardiology 58: 114C-116C, 1986 Barbey JT, Chaffin PL, Rigby S, Thompson KA, Echt OS, et at. Pharmacology of encainide metabolites in man. American Heart Association, 58th Annual Scientific Sessions. Circulation 72: 81 I I-S165, 1985 Barbey JT, Thompson KA, Echt OS, Woosley RL, Roden OM. Plasma concentration-response relations and disposition of encainide metabolites in man. Clinical Research 34: 394A, 1986 Bennett PB, Woosley RL, Hondeghem LM. Competitive interactions of lidocaine (L) and one of its metabolites, glycine xylidide (GX), with cardiac sodium channels. Circulation 764: 11-20, 1986 Bergstrand RH, Wang T, Roden OM, et at. Effect of liver disease on encainide disposition. World Conference on Clinical Pharmacology and Therapeutics, Washington, 1983, Abstract no. 60, American Society of Pharmacology and Experimental Therapeutics, 1983 Bergstrand RH, Wang T, Roden OM, Avant GR, Sutton WW, et at. Encainide disposition in patients with chronic cirrhosis. Oinical Pharmacology and Therapeutics 40: 148-154, 1986a Bergstrand RH, Wang T, Roden OM, Stone WJ, Wolfendon HT, el aI. Encainide disposition in patients with renal failure. Clinical Pharmacology and Therapeutics 40: 64-70, 1986b Blair lA, Sweetman BJ, Mayol RF. The polar urinary metabolites of encainide. Presented (Abstract no. 1286) at the 3rd World Congress on Clinical Pharmacology and Therapeutics, Stockholm, 1986 Carey EL, Duff HJ, Roden OM, Primm RK, Wilkinson GR, et at. Encainide and its metabolites: comparative effects in man on ventricular arrhythmias and electrocardiographic intervals. Journal of Clinical Investigation 73: 539-547,1984 Chesnie B, Podrid P, Lown B, Raeder E. Encainide for refractory ventricular tachyarrhythmia. American Journal of Cardiology 52: 495-500, 1983 Dawson AI(, Roden OM, DuffHJ, Woosley RL, Smith RF. Differential effects of O-demethyl encainide on induced and spontaneous arrhythmias in the conscious dog. American Journal of Cardiology 54: 654-658, 1984 Duff HJ, Dawson AK, Roden OM, Oates JA, Smith RF, et at. The electrophysiologic actions of O-demethyl encainide: an active metabolite. Circulation 68: 385-391, 1983 Elharrar V, Zipes DP. Effects of encainide and metabolites (MJ14030 and MJ9444) on canine cardiac Purkinje and ventricular fi~rs. Journal of Pharmacology and Experimental Therapeutics 220: 440-447, 1982 Fain ES, Dorian P, Davy J-M, Kates RE, Winkle RA. Effects of encainide and its metabolites on energy requirements for defibrillation. Circulation 73: 1334-1341, 1986 Gillis AM, Kates RE. Clinical pharmacokinetics of the newer antiarrhythmic agents. Clinical Pharmacokinetics 9: 375-403, 1984 Harrison DC, Kates RE, quart BD. Relation of blood level and
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metabolites to the antiarrhythmic effectiveness of encainide. American Journal of Cardiology 58: 66C-73C, 1986 Kates RE, Harrison DC, Winkle RA. Metabolite cumulation during long-term oral encainide administration. Clinical Pharmacologyand Therapeutics 31: 427-432, 1982 Lineberry MD, Davies RF, Chaffin PL, Lee JT, Echt OS, et at. Safety and efficacy of combining encainide and lidocaine. Circulation 76 (Suppt. IV): 511, 1987 Mayol RF, Gammans RE. Analysis of encainide in plasma by radioimmunoassay and high pressure liquid chromatography. Therapeutic Drug Monitoring I: 507-524, 1979 Quart BD, Gallo DO, Sami MH, Wood AJJ. Drug interaction studies and encainide use in renal and hepatic impairment. American Journal of Cardiology 58: I04C-113C, 1986a Quart B, Durkee J, Soyka L. Polymorphic encainide oxidation: what is the clinical significance? Acta Pharmacologica Toxicologica 59 (Suppt. V): 116 (Abstract 333), 1986b Roden OM, DuffHJ, Altenbern 0, Woosley RL. Antiarrhythmic efficacy of the O-demethyl metabolite of encainide. Journal of Pharmacology and Experimental Therapeutics 221: 552-557, 1982 Roden OM, Dawson AI(, DuffHJ, Woosley RL, Smith RF. Electrophysiologic effects of O-demethyl encainide in a canine model of sustained ventricular tachycardia. Journal of Cardiovascular Pharmacology 6: 588-595, 1984 Siddoway LA, Thompson KA, McAllister CB, Wang T, Wilkinson GR, et at. Polymorphism ofpropafenone metabolism and disposition in man: clinical and pharmacokinetic consequences. Circulation 75: 785-791, 1987 Smith RL. Polymorphic metabolism of the Il-adrenoceptor blocking drugs and its clinical relevance. European Journal of Clinical Pharmacology 28: 77-84, 1985 Wang T, Roden OM, Wolfenden HT, Woosley RL, Wood AJJ, et at. Influence of genetic polymorphism on the metabolism and disposition of encainide in man. Journal of Pharmacology and Experimental Therapeutics 228: 605-611, 1984 Winkle RA, Peters F, Kates RE, et at. Clinical pharmacology and antiarrhythmic efficacy of encainide in patients with chronic ventricular arrhythmias. Circulation 64: 290-296, 1981 Winkle RA, Peters F, Kates RE, Harrison DC. Possible contribution of encainide metabolites to the long-term antiarrhythmic efficacy of encainide. American Journal of Cardiology 51: 1182-1188, 1983 Woosley RL, Roden OM, Cain MA, Dai GF, Wang T, et at. Coinheritance of the polymorphic oxidative metabolism of encainide and debrisoquine. Clinical Pharmacology and Therapeutics 39: 282-289, 1986
Authors' address: Dr Dan M. Roden, Department of Pharmacology, School of Medicine, Vanderbilt University, 1161 21st Avenue, Nashville, TN 37232 (USA).