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Comparative pharmacokinetics of new antiarrhythmic drugs
The importance of pharmacokinetics to drug therapy is routinely accepted by many clinicians, and especially cardiologists, today. Certainly the pharmacokinetics of a rug are a consideration when a dosage regimen is being designed for a drug and may even be a factor when a choice an drug therapy is being made. A working knowledge of a drug’s pharmacokinetics can be essential in cardiology since the kinetics of the drug may be altered by the patient’s disease state or affected by the multiplicity of drugs the patients may be receiving. The objective of this report is to review the pharmacokmetics of several new antiarrhythmic agents. Unfortunately, there is a paucity of data on some of the new and possibly significant drugs For the most part these data have been abstracted from the literature. Certainly in the techniques are coming years, as new analytic developed, much of these data will be modified or viewed as incorrect. The basic principles of pharmacokinetics will not be reviewed here, since these have been covered satisfactorily in a recent review on antiarrhythmics.’ The pharmacokinetics of the established antiarrhythmics, iidocaine, inidine, and procainamide, will not be review in detail. Because of their short half-lives, neither of these prototypes has been satisfactory for once or twice daily administration. Therefore, on the basis of half--life alone, a new antiarrhythmic agent coda be a therapeutic improvement. Also, in the steady state each of these three drugs has metabolite levels that couPd contribute to their overall activity. The presence of an active metabolite certainReplintrequests: Robert A. Ronfeld, Ph.D.. Head of Drug Disposition, Astra Pharmaceutical Products, Inc., P.Q. Box 1089, Framingham, MA 01701.
ly will make the interpretation of clinical blood or plasma samples more difficult. Active metaboiites may also increase the interpatient dose-response variability. In the future there will very likely be a number of antiarrhythmics for the clinician to select from. The predictability and convenience of a dosage regimen may then be an important consideration in selecting an appropriate chug.
Tocainide and Iidocaine have similar pharmaogic and electrophysiologic properties. Tocainis less potent than lidocaine in direct cardiac effects and in central nervous system (CNS) effects. Tocainide is a primary am to the tertiary amine lidocaine, an the free base is 20 times less lipophilic in an 0ctanol:water system. Aside from potency, the major difference between lidocaine and tocainide resides in their pharmacokinetics. Tocainide has a II- to 1%how half-life in healthy volunteers.‘. ” In patients the mean half-life was also 13 hours, although the variability was greater than with the volunteers.4, j The plasma protein binding of tocainade was constant over the therapeutic range with approximately 50% bound2 The renal clearance of free drug was approximately eqluivalent to the ypically, expected glomerular filtration rate. 40% of an oral dose is excreted unchanged in the urine and 25% is excreted as a glucuronide conjugate of M-carboxytocainide.G Total body clearance in both patients and volunteers was 115 to 140 mllmin.‘~ 5 Plasma levels above 5 pg/ml are reported to be eiTective in reducing the frequency of premature ventricular beats.” Plasma concentrations above 5.0 and 8.3 pg/ml resulted, on the average, in 70% and 90% reductions in premature beats. ther
GOOZ-8703/80/130978 + 06$00.60/00 1980The C. Y. Mosby Co.
Pharmacokinetics
workers reported a 75% reduction in ventricular premature beats when the mean peak blood level was 10.3 pg/ml.:’ There are measurable levels of two metabolites in plasma, the previously mentioned glucuronide and lactoxylidide, which is the product of oxidative deamination.” Based on animal pharmacologic data, it appears that the metabolites do not contribute to the efficacy or CNS side effects of tocainide. Mexiletine
Mexiletine is, a primary amine, structurally similar to tocainide. Mexiletine has an ether linkage between the benzene ring and alkyl chain, whereas tocainide has an amide linkage. Because of this structural difference mexiletine has a higher pK, and much larger octanol-water partition coefficient. The half-life of mexiletine was 9 to 12 hours in volunteers.“. ’ In patients, mean half-lives of 12 and 13 hours were reported as well as a mean of 16.7 hours for patients with acute myocardial infarction. The volume of distribution was large and reported as 6.6 and 8.1 L/kg in patients and 500 to 660 L in volunteers.‘O, I1 Total body clearance was also large at 6.5 and 7.1 ml/mm/kg. There are conflicting reports on the importance of renal excretion. At a normal and unadjusted urinary pH, 8% to 20% was excreted unchanged. However, at a urine pH of 5, renal excretion increased to 40% to 60% and renal clearance increased by a factor of 3 to 4.“. I’ However, the effect of normal physiologic variation in pH remains contromversial.“, I3 At least in acute myocardial infarction (AMI) patients, there were large intersubject variations in plasma levels, with trough levels varying by an order of magnitude.‘” The oral absorption and plasma levels were significantly reduced when mexiletine was concomitantly administered with morphine or diamorphine.” This negative effect on absorption is probably not unique for mexiletine, and these investigators suggested that this may also occur with other drugs and antiarrhythmics. Effective plasma levels are reported to be 0.75 to 2.0 pg/ml. The incidence of side effects, including nausea, tremor, and hypotension, increased at plasma levels above 2.0 pg/ml. Mexiletine has been used botlh intravenously and orally and in the early stages of myocardial infarction. Assuming it is effective, there is an advantage to using
American
Heart
Journal
of new
antiarrhythmic
drugs
the same drug for initial intravenous administration and maintenance oral administration. Unfortunately, because of the narrow therapeutic range, the intravenous dosage schedules are complex.” Loreainide
Lorcainide is a new antiarrhythmic in which there have only been preliminary reports on its electrophysiologic and antiarrhythmic properties.‘” However, the pharmacokinetics of this new antiarrhythmic have been reported in detail. The terminal half-life in patients with chronic ventricular premature contractions was reported to be 7.7 hours by two separate groups of investigators.‘“, I7 There were dramatic differences among subjects with half-lives varying from 2.6 to 15.2 hours. The volume of distribution was very large at 8 to 10 L/kg. The plasma and blood clearances were 1,000 and 1,500 ml/min, respectively. Only a few percent of the dose was excreted unchanged in the urine. Since the clearance is approximately equivalent to liver blood flow, we would expect a large first-pass effect if metabolism occurs in the liver. Based on a single 100 mg oral dose, this assumption would appear correct, since only 4% of the dose was bioavailable. However, the bioavailability increased to 30% to 60% with a 200 mg dose and increased to 45% to 200% with multiple 100 mg doses. Apparently metabolic saturation occurs with oral administration. There are probably two factors contributing to this; the concentration presented to the liver can be much higher after an oral dose than after an intravenous dose, and at least with multiple dosing there may be product or metabolite inhibition. This dose-dependent bioavailability may also occur with drugs such as propranolol and alprenolol, which also have high hepatic clearances.‘“. I9 The primary metabolite in plasma appears to be a N-dealkylated lorcainide or norlorcainide. At steady state the norlorcainide:lorcainide ratio is approximately 3 with oral administration and 1 with intravenous administration.““, PIThe activity of both compounds, measured either as reduction in ventricular premature contractions (WCs) or QRS widening, was similar. An effective antiarrhythmic dose appears to be around 100 mg t.i.d., which resulted in steady-state plasma levels of 300 and 900 rig/ml for lorcainide and norlorcainide, respectively.
979
Aprindine is a Class I antiarrkytbmie agent and Bocd anesthetic. It has electrophysiologie properties similar to lidocaine, but exhibits greater potency. In twcu separate studies with volunteers, the average half-life was 22 h~ours, with a range of 12 to 66 lmurs.“~ 23However, ina patients, average half-lives of 43 and 50 hours with ranges of 20 to 110 hours were foundi’~ Za Analysis of the data from cane volunteer study, in which both cold and radiolabeled drugs were administered, implicated a 70% to 80% bioavdability.“’ This apparently wa3 due to first-pass metabolism since the totaB radioactivity in the plasma was idlentical for both oral and intravenous doses. The total body clearance in volunteers was approximateely l7O mUmin or 2.5 ml/min/kg. In patients, it appears to be substantially lower, possibly around 70 mUmin. Hasma levels effective in suppressing supraventricular or ventricular arrhythmias were generally from I to 2 ,~g/mP.‘” Minor side effects, most frequently dizziness, occurred in the 2 to 3 ygiml range. Primary metabolites reported have been hydroxylation cm the phenyl and inaanyl rings and iclesethylaprincaine~~‘~, “li 8 Di3opyramide is an established antiarrhythmic with electrophysiologic properties similar to quinidine. Half-lives in volunteers are generally reported to be 7.0 to 8.0 hours.‘:, 2yHowever, these half-lives may not be seal or meaningful, since the plasma protein binding of disspyramide changes dramatically with concentration, ana evenwithin the therapeutic range. It has been reported that free fraction in pPasma increased by 50% to 100% as total concentration increased over the therapeutic range.‘“-” Because of the nonlinearity in protein binding, total pllasma concentration and area unaer the plasma curve are not proportional to dose. However, the concentration of nonprotein-bound drug in plasma was proportional to dose.“1Pt appears that clearance is soley dependent on free arug, and consequently changes in protein binding do not affect the free concentration. The e free drug in plasma has been reported ts be 3.8 to 4.5 ho~rs.~‘. “’ Since the clearance of free drug is constant with doseand concentration, we would not expect changes in binding to be of any consequence to the pharma-
cologic activity. owever, this makes interpretation and dosage adjustment based on tot24 plasma concentration very dYfEcult. The determination of free concentration is not a routine proeedure in most laboratories. The therapeutic range for a~so~yra~~a~ in terms of total concentration is reportedly 2 to 7 pg/m13” Disopyramide phosphate (Norpace) had an 80% to 9B)%‘8~“. 34.35 bioavailabdity when oral versus intravensus pL~3ma levels were used as a criterion 90% when urinary excretion was usedZfi. “’ cause of its short half-life, it is generailly administered at 6- or $-hour intervals. However, a -release product has been developed ws for a 12”hour dosage schedule.“” Approximately 58% to 60% of an intravenous or oral dose can be recovered as unchanged drug in the urine.“, ToThe major metabolite appears to be N-deisopropyldisopyramide, which accounts for another 25% of the dose in urine. At steady state, the plasma levels of the metabolhte were approximately one third of the parent compound.“” era
ii
Verapamil has been recognized as an antiarrhythmic agent for many years, Even before specific analytic methods were developed, it was recQgniZed that the drug was probably rapidly metabolized since the effective oral dose was 10 to 15 times the required intravenous dose.:37 Although there has been extensive work on the pharmacology and electrophysidogy of this compOui2a,there is a paucity of data on its pharmaeokinetics. The only complete report indicates that it has a half-life of 3 to 4 hours following a 10 mg intravenous aOd8 The total body plasma clearance in three subjects, 59 to 69 years of age, varied from 730 to 1,120 ml/min (mean 12.6 ml/min./kg). Only 5% of the d0se was excreted unchanged in the urine. Although it was not done in a crossover fashion, the apparent bioavailability was 0nEy 10% to 20% following an 80 mg oral dose. This low availability was apparently due to a large first-pass elect since, based on radio&ivsty, absorption was complete. The volume of distribution was large, at 6.0 L/kg and the plasma protein binding was 90%. As with other drugs with large hepatic clearances, such as lorcainide and propranolol, we would expect a large intersubject variability in plasma levels foHowing oral administration.
December,
1980,
Vol.
100. No.
6. nart
2
Pharmacokinetics
Table
I. Pharmacokinetic T,h* fhr)
Antiarrhythmics Quinidine Procainamide Lidocaine Tocainide Mexiletine Aprindine Lorcainide Verapamil Disopyramide Total Free Bretylium Flecainide *T% = elimination tVd = apparent
parameters of antiarrhythmics V4 (L/W
Bioavailability m
Renal excretion
(%)
Reference
2.5 2.9 1.6 2.8 6.6 4.0 7.9 5.9
4.7 9.0 10.0 2.4 6.6 1.0 16.1 12.6
70 75 30 95 85 75 2-200 12
20 60 5 40 10 2 2 2
44 45 46 See text See text See text See text See text
7.0 4.0 7.8 14.0
0.5
0.9
85
55
See text
1.3
12.1
25 95
77
41 42
(Vdp
or Vd,,,,).
Summary
Table I lists pharmacokinetic parameters for eight of the drugs discussed as well as for quinidine, procainamide, and lidocaine. Data for two of the new agents, bretylium4’ and flecainide,.‘2 were not discussedin the text. If possible, these values are from patients. Obviously the individual values, especially those in the critically ill patients, may differ considerably from the mean values listed. Also with a drug such as lidocaine, there is a growing amount of evidence suggesting that clearance andi the elimination rate constant decrease for patients receiving infusions longer than 24 hours.‘” As stated ea.rlier, the three older drugs, quinidine, procainamide, and lidocaine, all have less than ideal pharmacokinetic properties for easily maintaining constant blood levels. Of course one solution to this has been to develop sustainedrelease dosage forms. Of the new drugs listed, tocainide, mexiletine, aprindine, and flecainide all have high bioavailability and a half-life that may
Journal
drugs
6.3 3.0 1.8 13.0 13.0 50.0 7.7 3.0
half-life. volume of distribution
Heart
antiarrhythmic
in man
Clearance (ml/minlkg)
There are several metabolites, with the N-demethylated compound apparently the major metabolite in plasma.“8 At steady state, this metabolite (norverapamil) and verapamil have approximately equivalent plasma levels.“” It has been suggested that the therapeutic plasma levels are in the range of 100 to 400 ng/m1.39 All of the metabolites are less potent than verapamil. Norverapamil had the greatest potency, with a 4.6 less vasodilating potency than verapamil.‘”
American
of new
allow for twice daily administration. The feasibility of twice daily administration depends on the therapeutic range and the difference between the maximum and minimum concentrations. For a half-life of 12 to 14 hours, we could expect a 1.5 to 2.0 ratio in maximum to minimum concentrations. With disopyramide, a half-life is listed for both free and total drug. Also volume of distribution and clearance are given for total disopyramide, in order to be consistent and comparable with the other drugs listed. As discussed earlier, the value for free disopyramide is the most meaningful. With both verapamil and lorcainide, there is a potential for a large first-pass metabolism. However, in the case of lorcainide, apparent metabolic saturation results in an apparent 100% bioavailability. These pharmacokinetic data may or may not be used in a clinical setting. Very possibly though, a blood or plasma sample will be sent to the laboratory for drug analysis. When obtaining a drug level, questions to ask yourself or the laboratory might be: (1) Is the value reliable; was the assay method specific; and could the blood sampling tube or technique lead to a false value? (2) How can these data along with other clinical and symptomatic data be used to stabilize or improve therapy? REFERENCES
1.
Harrison kinetics 20:217,
DC, Meffin PJ, Winkle RA: Clinical pharmacoof antiarrhythmic drugs. Prog Cardiovasc Dis 1977.
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2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Lalka 13, Meyer MB, Duce BR, Elvin AT: Kinetics of the oral antiarrhythmic Bidocaine congener, tocainide. Chn Pharmacol Ther 19:757, 1976. Graffner C, Conradson T, Hofrendabl S, Ryden L: Tocainide kinetics after intravenous and oral administration in healthy subjects and in patients with acute myocardial infarction. Clin Pharmacol Ther 27:64, 1980. Winkle RA, Meffin PJ, Fitzgerald JW, Harrison DC: Chnical efficacy and pharmacokinetics of a new orally effective antiarrbythmic, tocainide. Circulation 54:884, 1976. Ronfeld RA, Wolshin EM, Block AJ: Tocainide and metabolites: Human pharmacokinetics and animal pharmacology. Clin Pharmacol Tber 27:282, 1980. Elvin AT, Keenaghan JB, Byrnes EW, Tentborey PA, ?&Master PD, Takman BH, Lalka D, Manion CV, Baer DT, Wolshin EM, Meyer MB, Ronfeld RA: Tocainide conjugation in humans: Novel biotransformation pathway for a primary amine. J Pharm Sci 69:47, 19810. Ryan W, EngSer R, LeWinter M, Karliner JS: Efficacy of a new oral agent (tocainide) in the acute treatment of refractory ventricular arrhythmias. Am J Cardiol43:285, 1979. Prescott LF, Pottage A, elements JA: Absorption, distribution and elimination of mexiletine. Postgrad Med J 53(SLlppl. 1):50, 1977. Campbell NPS, Kelly JG, Adgey AAJ, Shanks RG: Mexiletine in normal volunteers. Br 3 Clin Pharmacol 6:372, 1978. Campbell NPS, Kelly JG, Adgey AAJ, Shanks RG: The chnical pharmacology of mexiletirte. Br J Clin Pharmacol 6:103, 1978. Paalman ACA, Roos JC, Siebelink J, Dunning AJ: Development of a dosage scheme for simultaneous intravenous and oral administration of mexiletine. Postgrad Med J 5qsupp1. 1):128, 1977. Ki$die MA, Kaye CM, Turner P, Shaw TRD: The influence of urinary pH on the elimination of mexiletine. Br J Clin Pharmacol 4 :229, 1974. Johnston A, Burgess CD, Warrington SJ, Wadsworth J, Hamer NAJ: The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers. Br J CIin Pharmacol 8:349, 1979. Pottage A, Campbell RWF, Achuff SC, Murray A, Juiian DG, Prescott LF: The absorption of oral mexiletihe in coronary care patients. Eur J Clin Pharmacol 13:393, 197s. Carmeliet E, Janssen PAJ, Marsboom R, van Neuten JM, Xhonneux R: Antiarrhythmic, electrophysioiogical and bemodynamic effects of lorcainide. Arch Int Pharmacodyn *her 231:104, 1978, Jahnchen E. Bechtolcl H. Kasaer W. Kerstins F. Just H. Heykants J,‘Meinertz T:‘Lorcainide. I. Saturable presys: temic elimination. Clin Pharmacol Tber 26:187, 1979. Klotz U, Muller-Seydhtz P, Heimburg P: Pharmacokinetics of lorcainide in man: A new antiarrhythmic agent. Clin Pharmacokinet 3:407, 1978. Shand DG, Rangno RE: The disposition of propranolol I: Elimination during oral absorption in man. Pharmacology 7:1x4, 1972. Ablad B, Ervik M, Hallgren J, Johnsson G, Solve11 E: Pharmacological effects and serum levels of orally administered alprenolol in man. Eur J Clin Pharmacol 5~44, 1972. Meinertz T, Kasper W, Kersting F, Just H, Be&told H, Jahnchen E: Lorcainide. II. Plasma concentration-effect relationship. Clin Pharmacol Ther 26:196, 1979.
21.
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
33. 34.
35.
36.
37. 38.
39.
40.
41.
Klotz U, Mulier-Seydlitz P, Heimburg P: Disposition and antiarrhythmic effect of lorcainide. Int J Clin Pharmacol Biopharm 117:152, 1979. DeIcr0ix C, Martin L, Van Durme JPy Kesteloot H, Hagemeijer F, Mbuyamba P, Deblecker M: Model for exchange kinetic5 of aprindine in man &ter single and multiple doses. Ameta Cardiol Suool. 18~177. , 1974. Do&n L, de Sway YM, Debiecker M, Georges A: Caracteristiques pharmacocmetioues et biodeeradation de laprindine chez I’homme. Therapie 29:221, i974. Hagemeijer F: Absorption, half-life, and toxicity of oral aprindine in patients with acute myocardial infarction. Eur J Clin Pharmacol 9:2P, 1975. Van Durme JP, Bogaert MG, Rossee? M-T: Therapeutic effectiveness and plasma levels of aprindine, a mew antidysrhythmic drug. Eur J Clin Pharmacol 7:343, 1974. Murphy PJ: Metabolic pathways of aprindine. Acta Car&o1 Sunnl. l&131. 1974. Ranney RE, Dean RR, Karim A, Radzialowski FM: Disopyramide phosphate: Pharmacokinetic and oharmacologic relationships of a new antiarrhythmi; agent. Arch Int Pharmacodyn 4 91:162, 1971. Bryson SM, Whiting B, Lawrence JR: Disnpyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability. Br J Clin Pharmacol6:409, 1978. Hinderling PH, Bres J, Garrett ER: Protein binding and erythrocyte partitioning of disopyramide and its monodealkylated metabolite. J Pharm Sci 63:1684, 1974. Cunningham JL, Shen DD, Shudo I, Azarnoff DL: The effects of urine pH and plasma protein binding on the renal clearance of disopyramide. Clin Pharmacokinet il:373, 1977. Meffin PJ, Robert EW, Winkle RA, Harapat S, Peters FA, Harrison DC: Role of concentration-dependent plasma protein binding in disopyramide disposition. J Pharmacokinet Biopharm 7:29, 1979. Hinderling PH, Garrett ER: Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans. J Pharmacokinet Biopharm 4:199, 1976. Niarchos AP: Disopyramide: Serum level and arrhythmia conversion. AM HEART J 9257, 1976. Cmmingham JL, Shen DD, Shudo I, Azarnoff DL: The effect of non-linear disposition kinetics on the systemic availability of disopyramide. Br J Clin Pharmacol 5:343, 8978. Dubetz DK, Brown NN, Hooper WD, Eadie MJ, Tyrer JH: Disopyramide pharmacokinetics and bioavailability. Br J Clin Pharmacol 6:279, 1978. Forssell 6, Graffner 6, Nordlander R, Nyquist 0: Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets. Eur J Clin Pharmacol 4 7:209, 1980. Krikler DM: Verapamil in cardiology. Em J Car&o1 2:3, 1974. Schomerus M, Spiegelhalder B, Stieren B, Eichelbaum M: Physiological disposition of verapamil in man. Cardiovasc Res 10:605, 1976. Woodcock BG, Hopi R, Kaltenbach M: Yerapamii and norverapamil plasma concentrations during long-term therapy in patients with hypertrophic obstructive cardiomyopathy. J Cardiovasc Pharmacol 2~17, 1980. Neugebauer G: Comparative cardiovascular actions of verapamil and its major metabolites in the anaesthetised dog. Cardiovasc Res 123247, 1978. Narang PK, Adir J, Yacobi A, Josselson J, Sadler JH: Twenty-seventh National Meeting, Academy of Pharmaceutical Sciences, Nov 11-15, 1979, Kansas City MO.
Pharmacokinetics
42.
43.
44.
Conard GJ, Carlson GL, Frost JW, Ober RE: Human plasma pharmacokinetics of flecainide acetate (R-818), a new antiarrhythmic, following single oral and intravenous doses. Clin Pharmacol Ther 25:218, 1979. Le Lorier 3, Grenon D, Latour Y, Caille G, Dumont G, Brosseau A, Solignac A: Pharmacokinetics of lidocaine after prolonged intravenous infusions in uncomplicated myocardial infarction. Ann Intern. Med 87:700, 1977. Ueda CT, Hirschfeld DS, Scheinman MM, Rowland M,
American
Heart
Journal
45.
46.
of new
antiarrhythmic
drugs
Williamson BJ, Dzindzio BS: Disposition kinetics of quinidine. Clin Pharmacol Ther 19:30, 1976. Galeazzi RL. Benet LZ. Sheiner LB: Relationship between the pharmacokinetics and pharmacodynamici of procainamide. Clin Pharmacol Ther 20:278, 1976. Thomson PD, Melmon KL, Richardson JA, Cohn K, Steinbrunn W, Cudihee R, Rowland M: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 78:499, 1973.
983
ly will make the interpretation of clinical blood or plasma samples more difficult. Active metaboiites may also increase the interpatient dose-response variability. In the future there will very likely be a number of antiarrhythmics for the clinician to select from. The predictability and convenience of a dosage regimen may then be an important consideration in selecting an appropriate chug.
Tocainide and Iidocaine have similar pharmaogic and electrophysiologic properties. Tocainis less potent than lidocaine in direct cardiac effects and in central nervous system (CNS) effects. Tocainide is a primary am to the tertiary amine lidocaine, an the free base is 20 times less lipophilic in an 0ctanol:water system. Aside from potency, the major difference between lidocaine and tocainide resides in their pharmacokinetics. Tocainide has a II- to 1%how half-life in healthy volunteers.‘. ” In patients the mean half-life was also 13 hours, although the variability was greater than with the volunteers.4, j The plasma protein binding of tocainade was constant over the therapeutic range with approximately 50% bound2 The renal clearance of free drug was approximately eqluivalent to the ypically, expected glomerular filtration rate. 40% of an oral dose is excreted unchanged in the urine and 25% is excreted as a glucuronide conjugate of M-carboxytocainide.G Total body clearance in both patients and volunteers was 115 to 140 mllmin.‘~ 5 Plasma levels above 5 pg/ml are reported to be eiTective in reducing the frequency of premature ventricular beats.” Plasma concentrations above 5.0 and 8.3 pg/ml resulted, on the average, in 70% and 90% reductions in premature beats. ther
GOOZ-8703/80/130978 + 06$00.60/00 1980The C. Y. Mosby Co.
Pharmacokinetics
workers reported a 75% reduction in ventricular premature beats when the mean peak blood level was 10.3 pg/ml.:’ There are measurable levels of two metabolites in plasma, the previously mentioned glucuronide and lactoxylidide, which is the product of oxidative deamination.” Based on animal pharmacologic data, it appears that the metabolites do not contribute to the efficacy or CNS side effects of tocainide. Mexiletine
Mexiletine is, a primary amine, structurally similar to tocainide. Mexiletine has an ether linkage between the benzene ring and alkyl chain, whereas tocainide has an amide linkage. Because of this structural difference mexiletine has a higher pK, and much larger octanol-water partition coefficient. The half-life of mexiletine was 9 to 12 hours in volunteers.“. ’ In patients, mean half-lives of 12 and 13 hours were reported as well as a mean of 16.7 hours for patients with acute myocardial infarction. The volume of distribution was large and reported as 6.6 and 8.1 L/kg in patients and 500 to 660 L in volunteers.‘O, I1 Total body clearance was also large at 6.5 and 7.1 ml/mm/kg. There are conflicting reports on the importance of renal excretion. At a normal and unadjusted urinary pH, 8% to 20% was excreted unchanged. However, at a urine pH of 5, renal excretion increased to 40% to 60% and renal clearance increased by a factor of 3 to 4.“. I’ However, the effect of normal physiologic variation in pH remains contromversial.“, I3 At least in acute myocardial infarction (AMI) patients, there were large intersubject variations in plasma levels, with trough levels varying by an order of magnitude.‘” The oral absorption and plasma levels were significantly reduced when mexiletine was concomitantly administered with morphine or diamorphine.” This negative effect on absorption is probably not unique for mexiletine, and these investigators suggested that this may also occur with other drugs and antiarrhythmics. Effective plasma levels are reported to be 0.75 to 2.0 pg/ml. The incidence of side effects, including nausea, tremor, and hypotension, increased at plasma levels above 2.0 pg/ml. Mexiletine has been used botlh intravenously and orally and in the early stages of myocardial infarction. Assuming it is effective, there is an advantage to using
American
Heart
Journal
of new
antiarrhythmic
drugs
the same drug for initial intravenous administration and maintenance oral administration. Unfortunately, because of the narrow therapeutic range, the intravenous dosage schedules are complex.” Loreainide
Lorcainide is a new antiarrhythmic in which there have only been preliminary reports on its electrophysiologic and antiarrhythmic properties.‘” However, the pharmacokinetics of this new antiarrhythmic have been reported in detail. The terminal half-life in patients with chronic ventricular premature contractions was reported to be 7.7 hours by two separate groups of investigators.‘“, I7 There were dramatic differences among subjects with half-lives varying from 2.6 to 15.2 hours. The volume of distribution was very large at 8 to 10 L/kg. The plasma and blood clearances were 1,000 and 1,500 ml/min, respectively. Only a few percent of the dose was excreted unchanged in the urine. Since the clearance is approximately equivalent to liver blood flow, we would expect a large first-pass effect if metabolism occurs in the liver. Based on a single 100 mg oral dose, this assumption would appear correct, since only 4% of the dose was bioavailable. However, the bioavailability increased to 30% to 60% with a 200 mg dose and increased to 45% to 200% with multiple 100 mg doses. Apparently metabolic saturation occurs with oral administration. There are probably two factors contributing to this; the concentration presented to the liver can be much higher after an oral dose than after an intravenous dose, and at least with multiple dosing there may be product or metabolite inhibition. This dose-dependent bioavailability may also occur with drugs such as propranolol and alprenolol, which also have high hepatic clearances.‘“. I9 The primary metabolite in plasma appears to be a N-dealkylated lorcainide or norlorcainide. At steady state the norlorcainide:lorcainide ratio is approximately 3 with oral administration and 1 with intravenous administration.““, PIThe activity of both compounds, measured either as reduction in ventricular premature contractions (WCs) or QRS widening, was similar. An effective antiarrhythmic dose appears to be around 100 mg t.i.d., which resulted in steady-state plasma levels of 300 and 900 rig/ml for lorcainide and norlorcainide, respectively.
979
Aprindine is a Class I antiarrkytbmie agent and Bocd anesthetic. It has electrophysiologie properties similar to lidocaine, but exhibits greater potency. In twcu separate studies with volunteers, the average half-life was 22 h~ours, with a range of 12 to 66 lmurs.“~ 23However, ina patients, average half-lives of 43 and 50 hours with ranges of 20 to 110 hours were foundi’~ Za Analysis of the data from cane volunteer study, in which both cold and radiolabeled drugs were administered, implicated a 70% to 80% bioavdability.“’ This apparently wa3 due to first-pass metabolism since the totaB radioactivity in the plasma was idlentical for both oral and intravenous doses. The total body clearance in volunteers was approximateely l7O mUmin or 2.5 ml/min/kg. In patients, it appears to be substantially lower, possibly around 70 mUmin. Hasma levels effective in suppressing supraventricular or ventricular arrhythmias were generally from I to 2 ,~g/mP.‘” Minor side effects, most frequently dizziness, occurred in the 2 to 3 ygiml range. Primary metabolites reported have been hydroxylation cm the phenyl and inaanyl rings and iclesethylaprincaine~~‘~, “li 8 Di3opyramide is an established antiarrhythmic with electrophysiologic properties similar to quinidine. Half-lives in volunteers are generally reported to be 7.0 to 8.0 hours.‘:, 2yHowever, these half-lives may not be seal or meaningful, since the plasma protein binding of disspyramide changes dramatically with concentration, ana evenwithin the therapeutic range. It has been reported that free fraction in pPasma increased by 50% to 100% as total concentration increased over the therapeutic range.‘“-” Because of the nonlinearity in protein binding, total pllasma concentration and area unaer the plasma curve are not proportional to dose. However, the concentration of nonprotein-bound drug in plasma was proportional to dose.“1Pt appears that clearance is soley dependent on free arug, and consequently changes in protein binding do not affect the free concentration. The e free drug in plasma has been reported ts be 3.8 to 4.5 ho~rs.~‘. “’ Since the clearance of free drug is constant with doseand concentration, we would not expect changes in binding to be of any consequence to the pharma-
cologic activity. owever, this makes interpretation and dosage adjustment based on tot24 plasma concentration very dYfEcult. The determination of free concentration is not a routine proeedure in most laboratories. The therapeutic range for a~so~yra~~a~ in terms of total concentration is reportedly 2 to 7 pg/m13” Disopyramide phosphate (Norpace) had an 80% to 9B)%‘8~“. 34.35 bioavailabdity when oral versus intravensus pL~3ma levels were used as a criterion 90% when urinary excretion was usedZfi. “’ cause of its short half-life, it is generailly administered at 6- or $-hour intervals. However, a -release product has been developed ws for a 12”hour dosage schedule.“” Approximately 58% to 60% of an intravenous or oral dose can be recovered as unchanged drug in the urine.“, ToThe major metabolite appears to be N-deisopropyldisopyramide, which accounts for another 25% of the dose in urine. At steady state, the plasma levels of the metabolhte were approximately one third of the parent compound.“” era
ii
Verapamil has been recognized as an antiarrhythmic agent for many years, Even before specific analytic methods were developed, it was recQgniZed that the drug was probably rapidly metabolized since the effective oral dose was 10 to 15 times the required intravenous dose.:37 Although there has been extensive work on the pharmacology and electrophysidogy of this compOui2a,there is a paucity of data on its pharmaeokinetics. The only complete report indicates that it has a half-life of 3 to 4 hours following a 10 mg intravenous aOd8 The total body plasma clearance in three subjects, 59 to 69 years of age, varied from 730 to 1,120 ml/min (mean 12.6 ml/min./kg). Only 5% of the d0se was excreted unchanged in the urine. Although it was not done in a crossover fashion, the apparent bioavailability was 0nEy 10% to 20% following an 80 mg oral dose. This low availability was apparently due to a large first-pass elect since, based on radio&ivsty, absorption was complete. The volume of distribution was large, at 6.0 L/kg and the plasma protein binding was 90%. As with other drugs with large hepatic clearances, such as lorcainide and propranolol, we would expect a large intersubject variability in plasma levels foHowing oral administration.
December,
1980,
Vol.
100. No.
6. nart
2
Pharmacokinetics
Table
I. Pharmacokinetic T,h* fhr)
Antiarrhythmics Quinidine Procainamide Lidocaine Tocainide Mexiletine Aprindine Lorcainide Verapamil Disopyramide Total Free Bretylium Flecainide *T% = elimination tVd = apparent
parameters of antiarrhythmics V4 (L/W
Bioavailability m
Renal excretion
(%)
Reference
2.5 2.9 1.6 2.8 6.6 4.0 7.9 5.9
4.7 9.0 10.0 2.4 6.6 1.0 16.1 12.6
70 75 30 95 85 75 2-200 12
20 60 5 40 10 2 2 2
44 45 46 See text See text See text See text See text
7.0 4.0 7.8 14.0
0.5
0.9
85
55
See text
1.3
12.1
25 95
77
41 42
(Vdp
or Vd,,,,).
Summary
Table I lists pharmacokinetic parameters for eight of the drugs discussed as well as for quinidine, procainamide, and lidocaine. Data for two of the new agents, bretylium4’ and flecainide,.‘2 were not discussedin the text. If possible, these values are from patients. Obviously the individual values, especially those in the critically ill patients, may differ considerably from the mean values listed. Also with a drug such as lidocaine, there is a growing amount of evidence suggesting that clearance andi the elimination rate constant decrease for patients receiving infusions longer than 24 hours.‘” As stated ea.rlier, the three older drugs, quinidine, procainamide, and lidocaine, all have less than ideal pharmacokinetic properties for easily maintaining constant blood levels. Of course one solution to this has been to develop sustainedrelease dosage forms. Of the new drugs listed, tocainide, mexiletine, aprindine, and flecainide all have high bioavailability and a half-life that may
Journal
drugs
6.3 3.0 1.8 13.0 13.0 50.0 7.7 3.0
half-life. volume of distribution
Heart
antiarrhythmic
in man
Clearance (ml/minlkg)
There are several metabolites, with the N-demethylated compound apparently the major metabolite in plasma.“8 At steady state, this metabolite (norverapamil) and verapamil have approximately equivalent plasma levels.“” It has been suggested that the therapeutic plasma levels are in the range of 100 to 400 ng/m1.39 All of the metabolites are less potent than verapamil. Norverapamil had the greatest potency, with a 4.6 less vasodilating potency than verapamil.‘”
American
of new
allow for twice daily administration. The feasibility of twice daily administration depends on the therapeutic range and the difference between the maximum and minimum concentrations. For a half-life of 12 to 14 hours, we could expect a 1.5 to 2.0 ratio in maximum to minimum concentrations. With disopyramide, a half-life is listed for both free and total drug. Also volume of distribution and clearance are given for total disopyramide, in order to be consistent and comparable with the other drugs listed. As discussed earlier, the value for free disopyramide is the most meaningful. With both verapamil and lorcainide, there is a potential for a large first-pass metabolism. However, in the case of lorcainide, apparent metabolic saturation results in an apparent 100% bioavailability. These pharmacokinetic data may or may not be used in a clinical setting. Very possibly though, a blood or plasma sample will be sent to the laboratory for drug analysis. When obtaining a drug level, questions to ask yourself or the laboratory might be: (1) Is the value reliable; was the assay method specific; and could the blood sampling tube or technique lead to a false value? (2) How can these data along with other clinical and symptomatic data be used to stabilize or improve therapy? REFERENCES
1.
Harrison kinetics 20:217,
DC, Meffin PJ, Winkle RA: Clinical pharmacoof antiarrhythmic drugs. Prog Cardiovasc Dis 1977.
981
Ronfeld
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Lalka 13, Meyer MB, Duce BR, Elvin AT: Kinetics of the oral antiarrhythmic Bidocaine congener, tocainide. Chn Pharmacol Ther 19:757, 1976. Graffner C, Conradson T, Hofrendabl S, Ryden L: Tocainide kinetics after intravenous and oral administration in healthy subjects and in patients with acute myocardial infarction. Clin Pharmacol Ther 27:64, 1980. Winkle RA, Meffin PJ, Fitzgerald JW, Harrison DC: Chnical efficacy and pharmacokinetics of a new orally effective antiarrbythmic, tocainide. Circulation 54:884, 1976. Ronfeld RA, Wolshin EM, Block AJ: Tocainide and metabolites: Human pharmacokinetics and animal pharmacology. Clin Pharmacol Tber 27:282, 1980. Elvin AT, Keenaghan JB, Byrnes EW, Tentborey PA, ?&Master PD, Takman BH, Lalka D, Manion CV, Baer DT, Wolshin EM, Meyer MB, Ronfeld RA: Tocainide conjugation in humans: Novel biotransformation pathway for a primary amine. J Pharm Sci 69:47, 19810. Ryan W, EngSer R, LeWinter M, Karliner JS: Efficacy of a new oral agent (tocainide) in the acute treatment of refractory ventricular arrhythmias. Am J Cardiol43:285, 1979. Prescott LF, Pottage A, elements JA: Absorption, distribution and elimination of mexiletine. Postgrad Med J 53(SLlppl. 1):50, 1977. Campbell NPS, Kelly JG, Adgey AAJ, Shanks RG: Mexiletine in normal volunteers. Br 3 Clin Pharmacol 6:372, 1978. Campbell NPS, Kelly JG, Adgey AAJ, Shanks RG: The chnical pharmacology of mexiletirte. Br J Clin Pharmacol 6:103, 1978. Paalman ACA, Roos JC, Siebelink J, Dunning AJ: Development of a dosage scheme for simultaneous intravenous and oral administration of mexiletine. Postgrad Med J 5qsupp1. 1):128, 1977. Ki$die MA, Kaye CM, Turner P, Shaw TRD: The influence of urinary pH on the elimination of mexiletine. Br J Clin Pharmacol 4 :229, 1974. Johnston A, Burgess CD, Warrington SJ, Wadsworth J, Hamer NAJ: The effect of spontaneous changes in urinary pH on mexiletine plasma concentrations and excretion during chronic administration to healthy volunteers. Br J CIin Pharmacol 8:349, 1979. Pottage A, Campbell RWF, Achuff SC, Murray A, Juiian DG, Prescott LF: The absorption of oral mexiletihe in coronary care patients. Eur J Clin Pharmacol 13:393, 197s. Carmeliet E, Janssen PAJ, Marsboom R, van Neuten JM, Xhonneux R: Antiarrhythmic, electrophysioiogical and bemodynamic effects of lorcainide. Arch Int Pharmacodyn *her 231:104, 1978, Jahnchen E. Bechtolcl H. Kasaer W. Kerstins F. Just H. Heykants J,‘Meinertz T:‘Lorcainide. I. Saturable presys: temic elimination. Clin Pharmacol Tber 26:187, 1979. Klotz U, Muller-Seydhtz P, Heimburg P: Pharmacokinetics of lorcainide in man: A new antiarrhythmic agent. Clin Pharmacokinet 3:407, 1978. Shand DG, Rangno RE: The disposition of propranolol I: Elimination during oral absorption in man. Pharmacology 7:1x4, 1972. Ablad B, Ervik M, Hallgren J, Johnsson G, Solve11 E: Pharmacological effects and serum levels of orally administered alprenolol in man. Eur J Clin Pharmacol 5~44, 1972. Meinertz T, Kasper W, Kersting F, Just H, Be&told H, Jahnchen E: Lorcainide. II. Plasma concentration-effect relationship. Clin Pharmacol Ther 26:196, 1979.
21.
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
33. 34.
35.
36.
37. 38.
39.
40.
41.
Klotz U, Mulier-Seydlitz P, Heimburg P: Disposition and antiarrhythmic effect of lorcainide. Int J Clin Pharmacol Biopharm 117:152, 1979. DeIcr0ix C, Martin L, Van Durme JPy Kesteloot H, Hagemeijer F, Mbuyamba P, Deblecker M: Model for exchange kinetic5 of aprindine in man &ter single and multiple doses. Ameta Cardiol Suool. 18~177. , 1974. Do&n L, de Sway YM, Debiecker M, Georges A: Caracteristiques pharmacocmetioues et biodeeradation de laprindine chez I’homme. Therapie 29:221, i974. Hagemeijer F: Absorption, half-life, and toxicity of oral aprindine in patients with acute myocardial infarction. Eur J Clin Pharmacol 9:2P, 1975. Van Durme JP, Bogaert MG, Rossee? M-T: Therapeutic effectiveness and plasma levels of aprindine, a mew antidysrhythmic drug. Eur J Clin Pharmacol 7:343, 1974. Murphy PJ: Metabolic pathways of aprindine. Acta Car&o1 Sunnl. l&131. 1974. Ranney RE, Dean RR, Karim A, Radzialowski FM: Disopyramide phosphate: Pharmacokinetic and oharmacologic relationships of a new antiarrhythmi; agent. Arch Int Pharmacodyn 4 91:162, 1971. Bryson SM, Whiting B, Lawrence JR: Disnpyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability. Br J Clin Pharmacol6:409, 1978. Hinderling PH, Bres J, Garrett ER: Protein binding and erythrocyte partitioning of disopyramide and its monodealkylated metabolite. J Pharm Sci 63:1684, 1974. Cunningham JL, Shen DD, Shudo I, Azarnoff DL: The effects of urine pH and plasma protein binding on the renal clearance of disopyramide. Clin Pharmacokinet il:373, 1977. Meffin PJ, Robert EW, Winkle RA, Harapat S, Peters FA, Harrison DC: Role of concentration-dependent plasma protein binding in disopyramide disposition. J Pharmacokinet Biopharm 7:29, 1979. Hinderling PH, Garrett ER: Pharmacokinetics of the antiarrhythmic disopyramide in healthy humans. J Pharmacokinet Biopharm 4:199, 1976. Niarchos AP: Disopyramide: Serum level and arrhythmia conversion. AM HEART J 9257, 1976. Cmmingham JL, Shen DD, Shudo I, Azarnoff DL: The effect of non-linear disposition kinetics on the systemic availability of disopyramide. Br J Clin Pharmacol 5:343, 8978. Dubetz DK, Brown NN, Hooper WD, Eadie MJ, Tyrer JH: Disopyramide pharmacokinetics and bioavailability. Br J Clin Pharmacol 6:279, 1978. Forssell 6, Graffner 6, Nordlander R, Nyquist 0: Comparative bioavailability of disopyramide after multiple dosing with standard capsules and controlled-release tablets. Eur J Clin Pharmacol 4 7:209, 1980. Krikler DM: Verapamil in cardiology. Em J Car&o1 2:3, 1974. Schomerus M, Spiegelhalder B, Stieren B, Eichelbaum M: Physiological disposition of verapamil in man. Cardiovasc Res 10:605, 1976. Woodcock BG, Hopi R, Kaltenbach M: Yerapamii and norverapamil plasma concentrations during long-term therapy in patients with hypertrophic obstructive cardiomyopathy. J Cardiovasc Pharmacol 2~17, 1980. Neugebauer G: Comparative cardiovascular actions of verapamil and its major metabolites in the anaesthetised dog. Cardiovasc Res 123247, 1978. Narang PK, Adir J, Yacobi A, Josselson J, Sadler JH: Twenty-seventh National Meeting, Academy of Pharmaceutical Sciences, Nov 11-15, 1979, Kansas City MO.
Pharmacokinetics
42.
43.
44.
Conard GJ, Carlson GL, Frost JW, Ober RE: Human plasma pharmacokinetics of flecainide acetate (R-818), a new antiarrhythmic, following single oral and intravenous doses. Clin Pharmacol Ther 25:218, 1979. Le Lorier 3, Grenon D, Latour Y, Caille G, Dumont G, Brosseau A, Solignac A: Pharmacokinetics of lidocaine after prolonged intravenous infusions in uncomplicated myocardial infarction. Ann Intern. Med 87:700, 1977. Ueda CT, Hirschfeld DS, Scheinman MM, Rowland M,
American
Heart
Journal
45.
46.
of new
antiarrhythmic
drugs
Williamson BJ, Dzindzio BS: Disposition kinetics of quinidine. Clin Pharmacol Ther 19:30, 1976. Galeazzi RL. Benet LZ. Sheiner LB: Relationship between the pharmacokinetics and pharmacodynamici of procainamide. Clin Pharmacol Ther 20:278, 1976. Thomson PD, Melmon KL, Richardson JA, Cohn K, Steinbrunn W, Cudihee R, Rowland M: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 78:499, 1973.
983