Metabolism of Flecainide

Transcription

1 Metabolism of Flecainide GORDON J. CONARD, PhD, and ROBERT E. OBER, PhD After oral administration in healthy human subjects, flecainide absorption is prompt (average peak level at 3 to 4 hours) and nearly complete (at least 90 % ); flecainide does not appear to undergo consequential presystemic biotransformation. Oral absorption in patients with cardiac arrhythmias, renal disease and congestive heart failure (CHF) is also good. Plasma levels of flecainide are proportional to dose within the therapeutic range. Neither food nor antacid affect the extent of flecainide absorption. In healthy subjects, the plasma half-life of unchanged flecainide is relatively long (mean 13 hours after single doses and 16 hours after multiple dosage). For patients with ventricular premature complexes, the half-life is longer (mean 20 hours), and twice-daily oral dosage is effective. The rate of flecainide elimination from plasma may possibly be reduced in older patients. Overall, the plasma pharmacokinetics of flecainide appear to be reasonably linear (not dose- or concentration-dependent). In humans, most (mean 86 % ) of a single oral dose is excreted in urine as flecainide and its metabolites; only a small portion (mean 5 % ) is found in feces. Thus, flecainide does not appear to undergo extensive biliary excretion. A substantial portion (mean 27 % ) of a dose is excreted in urine as unchanged flecainide. Under alkaline urinary conditions, flecainide elimination may be decreased. Only 2 major and 2 or 3 minor metabolites are found in human urine. The 2 major urinary metabolites possess little or no detectable antiarrhythmic activity and are also the major metabolites present in human From the Drug Metabolism Department, Riker Laboratories, Inc., Subsidiary of 3M, St. Paul, Minnesota. fatiicipating investigators: Donald B. Hunninghake, MD, University of Minnesota Medical School, Minneapolis, Minnesota; George P. Lewis, MD, Lemuel Shattuck Hospital, Boston, Massachusetts; Jeffrey L. Anderson, MD, University of Michigan Medical School, Ann Arbor, Michigan; Morrison Hodges, MD, Hennepin County Medical Center and University of Minnesota, Minneapolis, Minnesota; Raymond L. Woosley, MD, PhD, Vanderbilt University School of Medicine, Nashville, Tennessee; Prof. Dr. med. H.-W. Klempt, Klinik Martinusquelle, Bad Lippspringe, Federal Republic of Germany; Ralph E. Cutler, MD, Veterans Administration Medical Center and Loma Linda University, Loma Linda, California; Joseph A. Franciosa, MD, Veterans Administration Hospital and University of Pennsylvania, Philadelphia, Pennsylvania; Albert Cohen, MD, Peninsular Testing Corporation, Miami, Florida; Prof. Paul Turner, MD, St. Bartholomew s Hospital, London, England; T. Budya Tjandramaga, MD, PhD, and Paul J. De Schepper, MD, PhD, Katholieke Universiteit, Leuven, Belgium; Paul G. Hugenholtz, MD, Thoraxcentrum, Rotterdam, Netherlands. Address for reprints: Gordon J. Conard, PhD, Drug Metabolism Department, Riker Laboratories, Inc., 3M Center, Building , St. Paul, Minnesota plasma (primarily conjugated); since free metabolite levels are very low in plasma, metabolites are not likely to contribute any consequential pharmacologic activity. The rate of flecainide elimination from plasma is somewhat slower in patients with moderate renal failure and in patients with CHF than that for healthy persons, and is markedly slower in some patients with end-stage renal disease. Urinary excretion of unchanged flecainide is somewhat less in moderate renal patients and is markedly less in end-stage renal patients, but is not altered in CHF patients. Dosage should be reduced in patients with more severe renal disease and, if indicated, in some CHF patients. Hemodialysis is not an effective means for removal of unchanged flecainide, but does provide more substantial removal of metabolites. Flecainide is not extensively bound (mean 40 % ) to human plasma proteins in vitro and binding is independent of total drug level. Thus, consequential drug-drug interactions in vivo based on protein binding effects are not expected, and it is unlikely that changes in plasma proteins would alter free drug levels to any clinically consequential extent. Therapeutic plasma levels of flecainide (associated with greater than 90% suppression of ventricular premature complexes) range from about 200 to 1,000 ng/ml (mean 500 ng/ml). Trough plasma levels up to about 1,500 ng/ml are generally well tolerated in most patients, but consequential adverse experiences may occur at lower levels in some patients with more serious cardiovascular disease. (Am J Cardiol 1984;53:418-51B) Flecainide (Tambocofl, U.S. adopted name, flecainide acetate, R-818) has been extensively investigated in many clinical trials. Flecainide provides sustained suppression of ventricular arrhythmias with twice-daily oral dosage in most patients1-7 and is effective when given intravenously.s-lo Comprehensive metabolic information has been obtained for flecainide in humans and laboratory animals. Summary results and conclusions on the metabolic disposition of flecainide are described in this report, with emphasis on human data; animal results that are relevant to human safety considerations are also included. This review brings together related data from many studies and thus provides a broad perspective. Bioanalytical Methods For all clinical studies, the concentrations of unchanged flecainide in human plasma and urine were

2 428 METABOLISM OF FLECAINIDE measured by use of a sensitive and specific gas-liquid chromatographic method with electron capture detection and an internal standard for quantitation.lljs As an alternative to this research method, a much less complex and more rapid method using a bonded-phase column extraction procedure and high-performance liquid chromatography (HPLC) is available for therapeutic monitoring of plasma flecainide levels. J4 Other HPLC15J6 and spectrophotofluorometric17j8 methods for flecainide have also been reported. Plasma Pharmacokinetics During safety/metabolic (phase I) and efficacy (phase II) studies, the pharmacokinetics of flecainide elimination from plasma have been assessed in healthy subjects and in patients with ventricular premature complexes (VPCs). Results from several studies show that the plasma half-life of unchanged flecainide is relatively long in both healthy subjects and patients with VPCs. Intravenous dosage: After a single i.v. dose, plasma levels of flecainide decrease rapidly during the initial 15 to 30 minutes after dosagelg; after this initial phase, which reflects rapid distribution of drug from the systemic circulation to tissues, the rate of flecainide disappearance from plasma is relatively slow during the terminal elimination phase. For 16 male subjects in 2 studies,lsjo the terminal phase plasma half-life of flecainide ranges from 7 to 19 hours (mean 13 hours) with single i.v. doses of 0.5 to 2.0 mg/kg (Table I). For 8 of these subjects,lg plasma (total body) clearance ranges from 4.6 to 12.1 ml/min/kg (mean 7.6) and apparent volume of distribution ranges from 5.0 to 13.4 liters/kg (mean 8.7). This large volume of distribution for flecainide is similar to those found with many basic (amine) compounds and probably reflects extensive distribution of unchanged drug from plasma to tissues. Single oral dosage: After a single oral dose to healthy subjects, flecainide appears promptly in plasmalg; after absorption is complete, the elimination of drug from plasma is relatively slow. For 79 subjects (78 men and 1 woman) in 6 studies,1gjm24 the plasma half-life of flecainide ranges from 7 to 22 hours with single oral doses of 60 to 240 mg (Table I); the overall mean half-life is about 13 hours and values are in reasonably good agreement among studies. For the 8 subjects in study 005 who received both i.v. and oral doses,ls half-life in a given subject is comparable after each dosage route (Table I), In addition, plasma half-life appears to be independent of dose (0.5 to 3.5 mg/kg). Assuming complete oral absorption, which is reasonable for flecainide (see next section), plasma clearance and apparent volume of distribution were determined from plasma AUC values. With oral dosage (Table I),1sJ-24 plasma clearance ranges from 4 to 20 ml/min/kg (mean 10) in these subjects; apparent volume of distribution averages about 10 liters/kg. With respect to age, plasma half-life and clearance for the 9 subjects in study 039,22 who were older (range 46 to 60 years; mean 52), are in good agreement with corresponding values for the younger subjects (mean age

3 February 27, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume TABLE II Summary of Plasma Pharmacokinetic Data for Flecainide in Patients with Ventricular Premature Complexes Plasma Plasma Flecainide No. Half-lifei (hr) Clearances (ml/min/kg) Principal Dose of Study Investigator (mg bid) Pts+ Mean Range Mean Range 030-O 1 Anderson loo I Wash-out Hodges Wash-out Woosley Wash-out EG-084 Klempt , I Wash-out EG186 Klempt #I Wash-out Twice-daily oral dosage for 3 to 12 days. + Both sexes. t Terminal phase plasma half-life of unchanged flecainide. 5 Plasma clearance from area under plasma level vs time curve. 11 Blood sampling schedule did not permit determination of plasma clearance. 29 years) in the other 5 studies (Table I); thus, for these 9 subjects as old as 60 years, age does not appear to be a factor in the rate of flecainide elimination from plasma. Multiple oral dosage: In view of its relatively long plasma half-life, flecainide would be expected to accumulate in plasma with multiple dosage to steady-state levels within a few days. In study 018,21 this has been directly confirmed by measurement of plasma flecainide levels during 7 days of multiple oral dosage (80 to 180 mg twice daily) to 16 subjects. For these subjects (Table I), the plasma half-life was found to average 13 and 16 hours after the first and final doses, respectively; correspondingly, plasma clearance averages 7.3 and 6.9 ml/min/kg. Although half-life is somewhat longer, on an average, after multiple dosage, plasma clearance with multiple dosage is nearly equivalent to that after single doses for the same subjects. Thus, multiple dosage (up to 180 mg twice daily) for 7 days has no consistent or substantial influence on the rate of flecainide elimination from plasma (no apparent induction or inhibition of drug elimination processes). Using the superposition method, steady-state plasma levels were calculated for each of these 16 subjects from plasma levels after the initial dose; steady-state levels actually measured are in good agreement in most subjects with those that are predicted on the basis of pharmacokinetics. Thus, flecainide predictably accumulates in plasma with multiple dosage and no unexpected accumulation of drug occurs that would not be anticipated on the basis of the pharmacokinetic properties of the drug. In addition, for a drug with linear plasma pharmacokinetics, the ratio of the first dose plasma AUC (0 to infinity) to the AUC for 1 dosage interval at steady-state will be 1.0; for these 16 subjects, the AUC ratios range from 0.6 to 1.2 (mean 1.0). Thus, the plasma pharmacokinetics of flecainide appear to be independent of dose (or plasma concentration) and to be reasonably linear with multiple oral dosage regimens of 1.1 to 2.8 mg/kg twice daily. During long-term drug administration to patients with VPCs, no evidence of consistent increasing or de- creasing trends in plasma flecainide levels is apparent21 Patients with ventricular premature complexes: During several efficacy studies in patients with VPCs, the plasma half-life of flecainide was determined during the washout period after multiple-oral-dosage regimens (Table II); the half-life ranges from 12 to 30 hours (mean 20) in 48 patients of both sexes.1-4,s No difference in half-life between sexes exists; for the 30 patients in multicenter study 030,1-3 the mean value for each sex (15 males and 15 females) is 20 hours. For 11 of these 30 patients for whom plasma clearance could be determined (Table II),2 clearance ranges from 3.1 to 12.6 ml/min/kg (mean 6.2). These data confirm that flecainide, from a pharmacokinetic viewpoint, should be well suited for twice-daily dosage for the chronic treatment of cardiac arrhythmias; efficacy data confirm the effectiveness of twice-daily dosage in most patients with VPCS. -~ In comparison to plasma pharmacokinetic data for younger, healthy subjects (Table I), the plasma half-life of flecainide is longer and plasma clearance is slower, on an average, for the older patients with VPCs (Table II). In addition to older age, cardiovascular status and multiple dosage may contribute to the slower rate of flecainide elimination from plasma in these patients. When plasma half-life for the 30 patients in study 030 are plotted vs age (range 28 to 69 years), the half-life tends to be longer with increased age; however, no statistically significant correlation (r = 0.26, p = 0.17) exists between half-life and age for these data. Although not statistically significant, these results suggest that the rate of flecainide elimination from plasma may be reduced in older humans, as has been reported for some other drugs.25,26 Oral Absorption The rate and extent of flecainide absorption from both a capsule and a tablet formulation have been assessed in humans; the capsule has been used in many clinical trials, and the tablet has been used in more recent clinical studies and is the formulation for world-

4 440 METABOLISM OF FLECAINIDE TABLE III Summary of Time lo Peak Plasma Level Data for Flecalnide in Humans After Oral Dosage Time to Peak Plasma No. of Flecainide Level (hr) Principal Flecainide Study / Study Investigator Dose* (mg) Formulation Population PtS Mean f SD Range 005' : $22: BE BE2 Lewis Cohen 200 Lewis 200 Lewis 200 Cohen 200 Cohen 200 Cohen 200 Cohen 200 Tjandramaga Tjandramaga Tjandramaga Capsule+ Capsule ;;&$e Capsule Tablet Solution Tablet with food Tablet Subiects f f f :: 5.1 f :: 2.8 f f f :: f Tablet with food 200 Tablet f O-6 with antacid Franciosa 200 Capsule CHF f Capsule patients Woosley loo-250 bid Capsule VPC patients f Cutler 200 Capsule Moderate renal & O-8 failure patients Cutler 200 Capsule End-stage f renal-patients All single oral doses under fasting conditions, except as indicated for studies 049, 152-BE, and Capsule formulation has been used in many clinical trials. + Two-period crossover (capsule and tablet) study in the same 16 subjects. g Tablet formulation has been used in more recent clinical trials and Is the formulation for worldwide marketing. I1 Four-period crossover (capsule, tablet, solution and tablet with food) study in the same 18 subjects. 7 Crossover (fasting, with food, and with antacid) study in the same subjects. CHF = congestive heart failure; VPC = ventricular premature complex: SD = standard deviation. wide marketing. Plasma level data show that flecainide weight-matched subjects (mean 4.9 hours). In addition, absorption into the systemic circulation is reasonably absorption in patients with renal failure (study 038)27 prompt and nearly complete from both formulations. is reasonably prompt (Table III). Rate of absorption: As an index to absorption rate, time to peak plasma level data from several studies are summarized in Table III for both formulations. In healthy subjects under fasting conditions,1ej1-24 peak flecainide levels are attained within 1 to 8 hours (mean 4) with the capsule and within 0.5 to 6 hours (mean 3) with the tablet. Although the rate of absorption from the capsule is somewhat slower, on an average, than from the tablet, the extent of absorption is comparable for the 2 formulations; thus, any difference in rate of flecainide absorption between formulations is of no consequence for the multiple-dose efficacy studies in which they have been used. In study 049 (Table III),21 time to peak level for the tablet (mean 2.8 hours) is only slightly later (p >0.05) than that for a solution of flecainide (mean 2.2 hours). Thus, the tablet formulation provides prompt drug absorption. As shown in 2 studies (049 and 152-BE),21 when the tablet is given with food, flecainide absorption is only slightly slower (p >0.05) than under fasting conditions; with food, peak times average about 3 hours (Table III). In addition, an antacid (aluminum hydroxide) does not alter the rate of flecainide absorption (Table III).21 In patients with VPCs after multiple oral dosage (study ),2 time to peak level data (mean 3.6 hours) indicate that absorption is reasonably prompt (Table III). For 10 patients with congestive heart failure (CHF) in study 039,22 the rate of flecainide absorption (mean 5.0 hours) is similar to that in 9 healthy age- and Extent of absorption: For healthy subjects, intrasubject comparisons of oral and iv. plasma AUC values (0 to infinity) from 2 studies (005 and 105-BE)1g,21 indicate that most (average greater than 90%) of an oral dose (60 to 200 mg; fasting conditions) is absorbed (capsule and tablet) and delivered to the systemic circulation as unchanged flecainide (Table IV). Thus, flecainide absorption is nearly complete from both formulations and the drug does not appear to undergo any consequential presystemic biotransformation (first-pass effect) in humans. After a 200-mg oral dose of carbon-14-labeled flecainide to 4 human subjects,23*24 81 to 90% (mean 86) of the dose is recovered in the urine as total radioactivity; only 4 to 6% (mean 5) of the dose is excreted in feces. This further indicates that flecainide absorption is nearly complete. Absorption from both the capsule and tablet was also compared with that from a reference solution of flecainide under fasting conditions in 18 subjects (study 049)21; intrasubject comparison of plasma AUC values shows that the extent of absorption from both solid dosage forms is comparable (p >0.05) to that from a solution (Table IV). Similarly, the extent of absorption from the tablet is essentially identical (p >0.05) to that from the capsule, as shown in studies 026 and 049 (Table IV).21 The relation of plasma flecainide levels to dose was assessed using a correlation/regression analysis. After single oral doses (60 to 240 mg; 0.6 to 3.5 mg/kg) to 32

5 February THE AMERICAN JOURNAL OF CARDIOLOGY Volume TABLE IV Summary of Plasma AUC Data for Flecainide in Healthy Humans Plasma AUC Data (0 to infinity) Principal Flecainide No. of Study Investigator Dose* (mg) Treatment Comparison Mean Ratio f SD Difference Lewis Capsule vs i.v f 0.21 NS 105BE Tjandramaga 200! Tablet5 vs i.v f 0.071! NS 8:;:: Lewis Tablet vs capsule 1.00 f 0.16 NS Cohen 200 Tablet vs capsule 0.96 f Cohen 200 :: Tablet vs solution 0.93 f 0.17, : 8;;:: Cohen 200 Capsule vs solution 0.97 f 0.12 NS Cohen 200 :: Tablet (with vs 1.07 * NS without food) 152-BE* Tjandramaga Tablet (with vs 0.93 * 0.15ii NS without food) 152-BE Tjandramaga Tablet (with vs 0.96 f NS without antacid) All single doses under fasting conditions except as indicated. t Results of statistical comparison of treatment difference in plasma AUC values; NS indicates p >0.05. x Capsule formulation has been used in many clinical trials. 5 Tablet formulation has been used in more recent clinical trials and is the formulation for worldwide marketing. 11 Since plasma half-life was significantly (p <0.05) different between treatments, individual plasma AUC values were normalized for elimination rate. SD = standard deviation. subjects in studies 005 and 0181g,21 (Fig. 1) and following multiple oral dosage (80 to 180 mg twice daily; 1.1 to 2.8 mg/kg twice daily) to the 16 subjects in study 018,21 statistical analysis results show that plasma levels (AUC values) are linearly related to (p <O.Ol) and proportional to dose levels over a wide range. Similarly for 11 patients with VPCs (study ),2 plasma AUC values (1 dosage interval) are proportional to dose during washout after multiple dosage (100 to 250 mg twice daily; 1.4 to 4.2 mg/kg twice daily).21 Overall, absorption of unchanged flecainide into the systemic circulation is nearly complete from both the capsule and tablet, and the extent of absorption does not appear to be affected by dose level within the therapeutic range. Thus, oral dosage provides reliable plasma levels of drug. When the tablet is given with food, results (Table IV) from 2 studies (049 and 152-BE)21 show that the extent of flecainide absorption is comparable (p >0.05) to that under fasting conditions. Similarly, an antacid (aluminum hydroxide) does not alter the extent of flecainide absorption (Table IV).21 Since the plasma half-life is longer for patients with VPCs (Table II) than for healthy subjects (Table I), for interstudy/population comparisons the plasma AUC values were normalized for elimination rate to estimate the extent of flecainide absorption in patients. For 11 patients (study ),2 normalized AUC data (1 dosage interval after multiple dosage) indicate that, the extent of absorption is good. Similarly, normalized AUC data for 10 patients with CHF (study 039)22,and 20 patients with renal failure (study 038)27 show that neither of these disease states has any consequential influence on flecainide absorption. Biotransformation Chemically, flecainide is N-(2_piperidylmethyl)- 2,5-bis(2,2,2-trifluoroethoxy)benzamide (Fig. 2) as the acetate salt. In subjects, a substantial portion of a single oral dose is excreted in urine as unchang,ed drug (see next section). In addition, flecainide undergoes exten- sive biotransformation in humans and its metabolites are excreted mostly in urine.2s,24 Urinary metabolites: Radiochromatographic (TLC) analysis results for 4 subjects who received carbon- 14-labeled flecainide2s indicate that in addition to unchanged drug (largest fraction), only 2 major metabolites of flecainide and 2 or 3 very minor metabolites are present in human urine.23,24 As determined from comparative chromatographic and spectroscopic data for each metabolite isolated from human urine and for synthetic reference compounds, the 2 major urinary metabolites are meta-o-dealkylated flecainide and the meta-o-dealkylated lactam of flecainide (Fig. 2); each 0 I I I DOSE (mg/kg) FIGURE 1. Relation of plasma flecainide AUC to dose level (with least-squares line) for 32 healthy male subjects after single oral doses of 60 to 240 mg (studies 005 and 018; Lewis).

6 468 METABOLISM OF FLECAINIDE Ilecdlnido meta-odealkylated Iactam of flecainlde o=c!: N -CHz OCHzCF, FIGURE 2. Major pathways of flecainide biotransformation in humans. metabolite is found both in the free and conjugated (glucuronide or sulfate) forms. Thus, in humans, flecainide undergoes 0-dealkylation preferentially in the meta position, piperidine ring oxidation, and phenolic conjugation (Fig. 2). In laboratory animal models, meta-o-dealkylated flecainide has some detectable antiarrhythmic activity (about 20% relative to flecainide), while the lactam metabolite has no detectable activity.21p24 Metabolites in plasma: Plasma levels of total flecainide metabolites (total carbon-14 minus unchanged flecainide) are generally greater (l- to 2-fold) than the levels of unchanged fleeainide in humans at corresponding times later than 1 hour postdose.23v24 However, the levels of total metabolites in plasma decrease at a rate only somewhat slower than levels of unchanged flecainide. Radiochromatographic (TLC) analysis shows that the 2 major urinary metabolites are also the only 2 major metabolites present in human plasma and that they are both present in plasma primarily as conjugates.21 HPLC analysis for meta-o-dealkylated flecainide shows that the free (unconjugated) metabolite exists in plasma at very low levels (less than 20 ng/ml with single doses and less than 50 ngfml with multiple dosage) relative to unchanged flecainide levels, which in these same subjects/patients range from about 200 to 1,600 ng/ml21 Radiochromatographic data indicate that free levels of the lactam metabolite in plasma are similarly low after single doses.21 Thus, metabolites of flecainide are not likely to contribute consequential pharmacologic activity. Excretion Routes and extent: In 4 healthy human subjects (3 men and 1 woman),23!24 81 to 90% (mean 86) of a 200-mg oral dose of carbon-14-labeled flecainide2s is excreted in urine as flecainide and its metabolites (total radioactivity); only 4 to 6% (mean 5) of the dose is found in feces as radioactivity. Thus, flecainide does not undergo N i extensive biliary excretion in humans, unless reabsorption occurs after biliary elimination. Unchanged flecainide: A substantial amount of a single oral dose is excreted in human urine as unchanged flecainide. For 50 subjects (49 men and 1 woman) in 5 studies, to 50% (mean 27) of the dose is found in human urine as unchanged drug (Table V); most is excreted within 24 hours after the dose. For 30 of these subjects, renal clearance of flecainide averages about 175 ml/min and accounts for about 25% of total body (plasma) clearance; hepatic biotransformation most probably accounts for much of the remaining clearance from plasma. Since the renal clearance of flecainide is somewhat greater than normal values for inulin clearance (100 to 150 ml/min), some active renal secretion of the drug may occur in humans. Overall, renal excretory processes contribute extensively to the elimination of flecainide and its metabolites in humans. In a separate study to assess the influence of urinary ph on flecainide elimination,2g 6 subjects received a single, 300-mg oral dose both under controlled acidic (ph about 5) and alkaline (ph about 8) urine conditions. Under very alkaline conditions, the extent of unchanged flecainide excretion in urine is markedly less and the rate of flecainide elimination from plasma is considerably slower. However, normal variations in urinary ph (5 to 7) would not be expected to greatly influence the elimination of flecainide. In the presence of very alkaline urine (ph greater than 7), which may result from some diets, concomitant medications or disease states, flecainide elimination may be slower, as has also been reported for other basic compounds,30-32 and flecainide dosage may need to be reduced. In addition, when urine is clearly alkaline, acidification of urine may promote flecainide elimination. Metabolites: Of the total radioactivity excreted in urine of the 4 subjects (mean, 86% of the dose) who received a dose of carbon-14-labeled flecainide,2 J4 35 to 50% (mean 42) of the dose is unchanged flecainide and 11 to 16% (mean 14) of the dose is total meta-o-dealkylated flecainide (free and conjugated). Radiochromatographic (TLC) analysis results indicate that a similar amount of the other major metabolite (lactam), a small amount (mean, 3% of the dose) of an unidentified acidic metabolite fraction, and trace amounts (less than 1% of the dose) of 2 other metabolite fractions are excreted in urine. The 2 major urinary metabolites are excreted in both the free and conjugated forms, but primarily as conjugates. For 16 subjects in study 026,21 urinary excretion of free and total meta-o-dealkylated flecainide accounts for, on an average, 4.6% and 18% of the dose within 96 hours, respectively. The half-life for renal elimination of this free metabolite is 12.6 hours, on an average, for these subjects; the average renal half-life for unchanged flecainide in these same subjects is 12.1 hours. Since metabolite formation occurred during the time that the half-life was estimated, the renal half-life estimate for the metabolite probably represents an overestimation. Thus, the free meta-o-dealkylated metabolite of fle- cainide is eliminated in humans at a rate comparable to or faster than that for unchanged flecainide.

7 February 27, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume Effect of Disease States on Pharmacokinetics and Excretion Congestive heart failure: To assess the influence of CHF on the elimination of flecainide from plasma and on its urinary excretion, 10 male patients with CHF (9 in New York Heart Association functional class III and 1 in class II) and 9 healthy male subjects (age- and weight-matched to the patients and free of cardiac disease) received a single, 200-mg oral dose. Plasma half-life (Table VI) averages 19 hours for the patients with CHF and 14 hours for the normal subjects (p <0.05); correspondingly, plasma clearance averages 8.1 and 10.2 ml/min/kg (p >0.05) for patients and subjects. For the CHF patients alone and for the patients plus subjects, neither plasma half-life nor plasma clearance is significantly correlated (p >0.05) with cardiac index. At 72 hours postdose (Table VI), the extent of urinary excretion of unchanged flecainide is equivalent in these patients with CHF (24.1% of dose) and age-matched subjects (24.7% of dose). Average renal clearance of flecainide is somewhat slower (p >0.05) in the patients with CHF (133 ml/min) compared with the subjects (176 ml/min), but it accounts for about 25% of total body (plasma) clearance in both groups. Since the rate of flecainide elimination from plasma of patients with CHF is only somewhat slower than that for healthy subjects and the extent of urinary excretion is equivalent with single doses, only modest downward adjustments, if any, in initial flecainide dosage for patients with CHF appear to be indicated. However, such results may not be predictive of those from continuous administration of flecainide, and downward adjustments in dose may be required in patients with left ventricular dysfunction as dictated in individual cases. Chronic renal function impairment: Because flecainide is extensively excreted in human urine, the possible effect of renal disease on the pharmacokinetics of flecainide elimination from plasma and on its urinary excretion was assessed in 10 patients (5 of each sex) with moderate chronic renal failure (creatinine clearances of 4 to 41 ml/min/m ) who were not undergoing hemodialysis and in 10 patients (5 of each sex; 1 anephric) with end-stage renal disease (creatinine clearances of 0 to 2 ml/min/m2) who were undergoing routine hemodialysis.27 After a single, 200-mg oral dose (Table VI), plasma half-life averages 17 hours in the group with moderate renal failure and 26 hours in the group with end-stage disease; correspondingly, plasma clearance averages 6.7 and 5.1 ml/min/kg in the 2 groups. For 2 of the patients in the group with end-stage disease, plasma half-life (51 and 58 hours) is markedly longer and plasma clearance (1.5 ml/min/kg) IS. considerably slower. Although the plasma pharmacokinetic data for renal disease patients (Table VI) markedly overlap corresponding results for subjects with normal renal function (Table I), average data from the renal patients indicate that flecainide elimination from plasma is slower in renal patients. Free (unconjugated) plasma levels of the meta-o-dealkylated

8 400 METABOLISM OF FLECAINIDE TABLE VI Summary of Plasma Pharmacokinetic and Urinary Excretion Data for Flecainide in Patients with Congestive Heart Failure and Renal Failure Study Population CHF patients 1 No. of / P&i* 10 9 Plasma Plasma Percent of Dose Half-life+ Clearancet Excreted as Unchanged (hr) (ml/min/kg) Flecainide Within 72 Hours Renal Clearances Mean Range Mean Range Mean Range (mllmin) Congestive heart failure (study 039,** Franciosa) to i Renal failure (study 038,27 Cutler) Moderate renal patients * End-stage renal patients t+ a Single 200-mg oral dose under fasting conditions. + Terminal phase plasma half-life of unchanged flecainide. t Plasma clearance from area under plasma level vs time curve. 5 Average renal clearance of unchanged flecainide. 11 All male CHF patients; 9 in NYHA functional Class Ill and 1 in Class II. n All male healthy subjects; age and weight-matched to the CHF patients. Moderate chronic renal failure patients (5 of each sex) with creatinine clearances of 4 to 41 ml/min/m* who were not on hemodialysis. f+ End-stage renal disease patients (5 of each sex; 1 anephric) with creatinine clearances of 0 to 2 ml/minim* who were all undergoing routine hemodialysis. tt Renal clearance could be estimated in only 4 of the 10 end-stage renal disease patients due to insufficient urine. ** Values for 8 of the 10 end-stage renal disease patients; 2 patients with very slow elimination from plasma were excluded. CHF = congestive heart failure; NYHA = New York Heart Association. metabolite are very low (less than 30 ng/ml) relative to unchanged flecainide in the moderate group21; although low (less than 45 ng/ml), levels of this metabolite persist longer in plasma of some patients with end-stage renal disease. At 72 hours after the dose (Table VI), the average cumulative excretion of unchanged flecainide in urine accounts for 15% of the dose in the group with moderate renal failure and for only 0.8% of the dose in the group with end-stage disease. Urinary excretion of the meta- 0-dealkylated metabolite (free and conjugated) accounts for 15% of the dose in the moderate group and is also markedly less (about 2% of the dose) in the endstage renal patients. 21 Compared with subjects with normal renal function (Table V), average renal clearance of flecainide is substantial, but slower in the moderate group (90 ml/min) and is very low in 4 of the end-stage patients (4 ml/min); on an average, renal clearance of flecainide accounts for about 17% and only 1.3% of total body (plasma) clearance in these moderate and end-stage renal disease patients, respectively. For these renal disease patients, both plasma and renal clearance of flecainide are significantly correlated (p <O.Ol) with urinary creatinine clearance; although plasma clearance appears to be reduced when creatinine clearance is lower, the latter alone is not a reliable predictor of plasma clearance for flecainide in a given patient. For elimination of unchanged drug from plasma, it appears likely that an increased extent of biotransformation can, to some extent, compensate for impairment of renal excretion of unchanged flecainide in some patients. Overall, for patients with moderate renal failure, the rate of flecainide elimination from plasma and the ex- cretion of unchanged drug in urine are somewhat less than those for healthy subjects; in addition, the excretion of flecainide in urine is markedly less in patients with end-stage renal disease and the rate of drug elimination from plasma is markedly slower in some patients with more severe impairment of renal function. Thus, and since metabolites of flecainide may accumulate in plasma with multiple dosage, an adjustment downward in drug dosage should be made for renal patients with creatinine clearances, conservatively, of 20 ml/min/m2 or less; dosage regimens should be decreased by 25 to 50%. At about 24 hours after dosage, the amount of unchanged flecainide removed in the dialysate during hemodialysis (about 3 to 5 hours) of patients in the end-stage renal disease group is very low (mean, 1% of the dose); the large volume of distribution for flecainide probably contributes to this small extent of removal. Thus, hemodialysis does not appear to be an effective means for removal of flecainide from the body. Removal of metabolites by hemodialysis (about 10% of the dose as total meta-o-dealkylated flecainide) appears to be more substantial.21 Plasma Protein Binding Flecainide binding to human plasma proteins was assessed in vitro using equilibrium dialysis; results indicate that flecainide is not extensively bound to human plasma proteins and that binding is independent of plasma drug level over a wide range that markedly exceeds therapeutic levels. Extent of binding: Heparinized human plasma (drug-free) from 8 healthy volunteers was dialyzed against a physiologic salt-buffer solution (ph 7.4) that

9 February 27, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume contained carbon-14-labeled flecainide for 16 hours (equilibrium) at results showed that flecainide is not extensively bound to human plasma proteins (average of 40% bound). With total plasma drug levels ranging from 15 to more than 3,400 ng/ml, the extent of flecainide binding to proteins ranges from 32 to 47%, but is independent of total drug level. Thus, free (unbound) levels of flecainide in plasma are proportional to total drug levels over a very wide range. The average extent of flecainide binding (range 35 to 42%) is consistent among subjects. In addition, heparin has no detectable influence on the in vitro binding of flecainide. Similar in vitro binding results have been reported from another study using equilibrium dialysis (4 hours at 37 C) and phosphate-buffered saline (ph 7.3) that contained carbon-14-labeled flecainide. 4J With serum from 6 healthy human subjects and over a wide range of flecainide levels in the buffer (200 to 10,000 ng/ml), the extent of flecainide binding is not related to drug concentration. In addition, serum from 97 subjects was dialyzed against buffer containing 1,500 ng/ml of flecainide. Overall, the extent of flecainide binding ranges from 37 to 58% (mean 48). Results show a significant (p <0.05) correlation between the fraction of flecainide bound and the serum tul-acid glycoprotein concentration, age of subjects and serum albumin concentration. Although flecainide binding, as with other basic drugs, is related to serum tul-acid glycoprotein concentration and, to a much lesser extent, to serum albumin level, the degree of dependence is such that very great changes in serum proteins would have to occur before the fraction of free drug would be appreciably altered. Thus, it is unlikely that changes in a patient s serum proteins would alter the serum binding of flecainide to a clinically significant extent. To determine the extent of flecainide binding to serum proteins of patients with acute myocardial infarcts, blood was obtained from 11 patients at daily intervals for 5 days after admission.zs On the first day, mean al-acid glycoprotein levels were elevated, and continued to increase; serum albumin and total protein levels were normal. Although the in vitro binding of flecainide to serum proteins of these patients on the first day (61 f 10%) is somewhat greater (p <O.Ol) than that for control subjects (48 f 4%),:s4J binding did not remain significantly high on subsequent days. Differences in protein binding of disopyramide during the 5 days after acute myocardial infarction have been reported. For flecainide, it is not likely that the small differences found in binding after a myocardial infarct would be of clinical importance. Effect of other drugs on flecainide binding: Since flecainide binding is not extensive and is independent of total plasma flecainide level, consequential interactions with other drugs based on protein binding effects would not be expected. However, using the procedures described above,:s an in vitro assessment of possible drug-drug interactions based on protein binding was completed with 10 other drugs that may be administered concomitantly with flecainide. Over a range of therapeutic plasma levels for fle- cainide (final levels about 300 to X00 &ml), the extent of flecainide binding in the presence of both therapeutic levels and S-fold therapeutic levels of 8 other drugs (digoxin, propranolol, practolol, quinidine, procainamide, disopyramide, diazepam and furosemide) is essentially identical to control values; at therapeutic levels of phenytoin and lidocaine, the extent of flecainide binding is comparable to control values and at 3-fold therapeutic levels of these 2 drugs, binding is only somewhat less (about 15%) than for controls. Thus, if given concomitantly with flecainide, none of these 10 drugs would be expected to produce consequential effects on t,he safety and efficacy of flecainide by influencing its plasma protein binding. Similarly, because flecainide is not extensively bound to human plasma proteins, it is not likely that flecainide will displace other protein-bound drugs to a great extent. Plasma Flecainide Levels Relative to Efficacy and Tolerance During an early, multiple-oral-dose efficacy study, 8 patients with VPCs received decreasing dosage regimens from 200 mg twice daily t,o 50 mg twice daily over 12 days. Results from concurrent plasma level monitoring suggest that minimal therapeutic plasma levels of flecainide for VPCs (associated with greater than 95% suppression) range from about 200 to 400 ng/ml. To better estimate the range of minimal therapeutic plasma levels for flecainide, VPC frequency was measured hourly during the placebo washout period after multiple oral dosage regimens (100 to 300 mg twice daily for 3 to 9 days) that were therapeutically effective in 30 patients from a multicenter study. -~: Plasma flecainide levels at the time of initial ret,urn of VPCs (to greater than 10% of baseline and to more than 30 VPCs/hour) during the washout period ranged from 200 to 1,000 ng/ml (mean 500). During a subsequent 2-week efficacy portion of these studies (100 to 300 mg twice daily), trough plasma levels of flecainide (12 hours postdose) at steady state ranged from about 300 to 1,600 ng/ml (mean 800) in these same 30 patients. These trough plasma levels were associated with a very high average degree of efficacy and were generally well tolerated (no consequential adverse reactions) in these patients with chronic VPCs and relatively mild cardiac disease. Recent experience in patients with more serious cardiovascular disease indicates that consequential adverse experiences may occur in some patients at the time when plasma flecainide levels are 700 to 1,000 ng/ml or greater.21 Experience in this patient group is limited; however, with continuing experience, more definitive conclusions should become evident. Animal Data Relevant to Human Safety Biotransformation (human/animal metabolite patterns): Long-term oral administration of flecainide to dogs (12 to 18 months), rats (2 years), and mice (18 months) in chronic toxicity studies does not produce any consequential toxic effects nor any evidence of carcinogenicity. As an indicator of the relevance of

10 508 METABOLISM OF FLECAINIDE these laboratory results to flecainide safety for humans, metabolite fractions in urine from these 3 animal species and in urine from humans after comparable single doses of carbon-14-labeled flecainide were compared.s7js Radiochromatographic (TLC) analyses of urine (both enzyme-hydrolyzed and nonhydrolyzed) were done using 3 solvent systems (1 acidic and 2 basic). Results indicate that flecainide undergoes more routes of biotransformation (more metabolite fractions) in each of the animal species than in humans. While at least 7 or 8 metabolite fractions are detectable in the urine of all 3 animal species, only 2 major metabolites and 2 or 3 minor ones are detectable in human urine. Although fewer metabolite fractions are found in human urine, all of the metabolite fractions in human urine are also present in the urine of all 3 animal species; in addition, the 2 major metabolite fractions in human urine and plasma (both the meta-o-dealkylated metabolite and the meta-o-dealkylated lactam of flecainide) are also major metabolite fractions in the urine from each of the 3 animal species. Conjugation of flecainide metabolites (glucuronide and/or sulfate) is a major route of biotransformation in all 4 species. Thus, the 3 chronic toxicity animal species were exposed to all of the same metabolites of flecainide as are present in human urine and plasma, and with regard to biotransformation, the evaluation of chronic drug toxicity in these animal species is a reasonable assessment of flecainide safety for humans. A species comparison shows that total metabolite levels (total radioactivity minus unchanged flecainide) in plasma, relative to unchanged drug levels, are much greater (2- to 25-fold) and more sustained in dogs and rats3gy4o than those (l- to 2-fold) in humans.23*24 For this reason and because all flecainide metabolites found in human urine are also present in dog and rat urine, it is very likely that both of these chronic toxicity species are systemically exposed to sustained levels of the same metabolites as are humans. This further supports the relevance of the results from the laboratory animal toxicity studies to the safety of flecainide for humans. Fetal exposure: To determine if rat fetuses are exposed to flecainide and its metabolites during multiple oral dosage, pregnant albino rats were dosed (20 mg/ kg/day) with carbon-14-labeled flecainide starting on gestation day 6.21 The presence of radioactivity in embryo-placenta and fetal tissues on gestation days 10 and 15 indicates that the lack of teratogenic effects in teratogenicity studies with flecainide in rats cannot be attributed to lack of exposure of the fetuses to flecainide and its metabolites during the period of organogenesis.21 Tissue levels and residues: After a single i.v. dose (5 mg/kg) of carbon-14-labeled drug to rats, flecainide and its metabolites (radioactivity) distribute extensively to many tissues, but not extensively to the brai+; subsequently, carbon-14 is eliminated at a relatively rapid rate (half-life of 2 to 4 hours). Although cardiac tissue levels of unchanged flecainide are 11- to 12-fold higher than plasma levels at corresponding times postdose, the levels of flecainide in heart and plasma decrease at the same rate (half-life of about 2 hours)40; thus, plasma levels reflect cardiac tissue concentrations of unchanged flecainide and this supports the use of monitoring plasma drug levels for correlation with pharmacologic or toxicologic activity in the heart. In rats, dogs, cats and monkeys, flecainide and its metabolites (carbon-14) do not appear to be retained in any tissues, except for pigmented ocular tissues.21je~40 In contrast to albino rats (nonpigmented eye), levels of carbon-14 (flecainide and its metabolites) are relatively high in the uveal tract of the 3 species (dog, cat and monkey) with pigmented eye tissues compared with nonpigmented eye tissues, other tissues and plasma. However, long-term toxicity studies in dogs (12 to 18 months), baboons (6 months), albino rats (2 years) and mice (18 months) have revealed no evidence of ocular toxicity, and no ocular toxicity has been found in hu- mans with administration of flecainide for 12 months and longer.21 In the cat, procainamide and its metabolites (carbon-14) are also present at relatively high levels in pigmented eye tissues and are also retained.41 Since procainamide is an antiarrhythmic drug for which there is a record of extensive chronic use in humans without ocular toxicity, these results with procainamide provide additional evidence of a lack of relation between drug binding to pigmented eye tissues and ocular toxicity.42 Overall, the presence and retention of flecainide and its metabolites in pigmented ocular tissues is judged to be of no clinical consequence to humans. Plasma pharmacokinetics: Compared with that in humans (Tables I and II), the plasma half-life of flecainide is relatively short in beagle dogs (about 1 hour),39 albino rats (about 2 hours),40 mongrel cats (about 1 hour),21 Yorkshire swine (about 1 hour),43 rhesus monkeys (about 4 hours)21 and yellow baboons (about 2 hours).21 Although the difference in plasma half-life for flecainide in humans as compared with laboratory animals is quantitatively striking, it is similar to the differences reported for several other drugs.44-4s For flecainide, no definitive, direct explanation for this difference can be given; however, available comparative data (presystemic biotransformation and excretion data) for dogs and rats3s140 indicate that this difference in plasma half-life between humans and animals most probably results, at least in part, from differences in rates of flecainide biotransformation (probably hepatic) and, perhaps, in the extent of biliary excretion. Apparently, these animal species possess drug-metabolizing-enzyme systems that can biotransform flecainide at a faster rate than in humans. Oral absorption: After oral dosage, flecainide absorption is prompt and nearly complete in dogs, rats and mice.21,3g,40 In contrast to humans, flecainide undergoes substantial presystemic biotransformation in dogs.3g For toxicity assessment, drug-diet feeding used for rodents provides extensive absorption and the solid dosage forms used for dogs provide nearly complete drug absorption.21y3g Excretion: Flecainide and its metabolites (radioactivity) are excreted in both urine and feces of dogs, rats and monkeys21,3g,40; the drug appears to undergo ex-

11 February THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53 51B tensive biliary elimination in dogs and rats. Only 1 to 2% of a single dose is excreted in dog urine as unchanged flecainide; in contrast, excretion of unchanged drug in rat urine accounts for about 25% of the dose and in mouse urine accounts for about 11 to 13% of a single dose. Acknowledgment: The authors acknowledge particularly the major collaborative involvement of Donald C. Kvam (Clinical Pharmacology) and the extensive bioanalytical contributions of Shaw F. Chang (Drug Metabolism) during the past 4 to 5 years. In addition, over the last 10 years, the following persons of the Riker Research Staff have contributed to these studies: Gary L. Carlson, Jeanne M. Fox, Kimberly F. Gibson, Sheila J. Gibson, Lester I. Harrison, Mary Jeanne Jernberg, James D. Johnson, Roy L. McQuinn, Aldora M. Miller, Gregory J. Quarforth, Charles E. Weeks and Teresa M. Welscher (Drug Metabolism); Terrance C. Coyne, Georg E. Cronheim, John W. Frost, Gary D. Gentzkow, H. Eric Lewis, Edwin F. McNichols and J. Peter Saunders (Clinical Research); Donald A. Berry and Terrance L. Fox (Research Data Operations); Ralph A. Heasley and James E. Tingstad (Pharmacy R and D); Elden H. Banitt and William R. Bronn (Chemistry); Jack R. Schmid (Pharmacology); and Marvin T. Case (Toxicology). References 1. Anderson JL, Stewarl JR, Perry BA, Van Hamersveid DD, Johnson TA, Conard GJ, Chang SF, Kvam DC, Pitt B. Oral fiecainide acetate for the treatment of ventricular arrhythmias. N Engi J Med 1981;305: Duff HJ, Roden DM, Maffucci RJ, Vesper BS, Canard GJ, Higgins SB, Oates JA, Smfih RF, Woosiey RL. Suppression of resistant ventricular arrhythmias by twice daily dosing with fiecainide. Am J Cardfol 1981;48: Hodges M, Haugiand JM, Granrud G, Conard GJ, Asinger RW, Mikeii FL, KreJci J. Suppression of ventricular ectopic depolarizations by fiecainide acetate, a new antiarrhythmic agent. Circulation 1982;65: , 4. Canard GJ, Cronheim GE, Kiempt HW. Relationship between plasma concentrations and suppression of ventricular extrasystoies by flecainide acetate (R-818). a new antiarrhythmic, in patients. Arzneim Forsch 1982;32: Fiecainide-Quinidine Research Group. Fiecainide versus quinidine for treatment of chronic ventricular arrhythmias: a multicenter clinical trial. Circulation 1983;67: Kiempi HW, Nayebagha A, Fabry E. Antiarrhythmic efficacy of mexiletine, propafenone and flecainide in ventricular premature beats: a comparative study in patients afler myocardial infarction. 2 Kardiol 1982;71: _._. 7. Kjekshus J, Baihen J, Orning 0, Storstein L. A double-blind crossover comparison of flecainide acetate and disopyramide phosphate in the treatment of ventricular premature complexes. Am J Cardioi 1984;53: Hoback J, Hodges M, Francis GS, Sharma B, Asinger RW. Flecainide (R-818) a new antiarrhythmic agent: effects on ventricular premature beats (abstr). Circulation 1978;58:suppi ll:li Somanf P. Antiarrhvthmic effects of flecainide. Clin Pharmacoi Ther 1980;27: Campbell RWF, Henderson A, Bryson LG, Reid DS, Sheridan DJ, Rawiins MD. Julian DG. intravenous flecainideoharmacokinetics and efficacv _.(abstr). Circulation 1981;64:suppi IV:IV Johnson JD, Carison GL, Fox JM, Miller AM, Chang SF, Conard GJ. Quantitation of flecainide acetate (R-818) a new antianhythmic, in biological fluids by gas chromatography with electron capture detection (abstr). In: Abstracts from the 183rd American Chemical Society National Meeting, Las Vegas, NV, Johnson JD, Carison GL, Fox JM, Miller AM, Chang SF, Conard GJ. Quantitation of fiecainide acetate (R-818) a new antianhythmic, in biological fluids by gas-liquid chromatography with electron capture detection. J Pharm Sci, in press. 13. Chang SF, Miller AM, FOX JIM, Weischer TM. 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Relation between bindinq to olasma orotein. aooarent volume of distribution. and rate constants oidispositionand elimination for chlororomazine in three soecies. J Pharm Pharmacol 1972:24: Harrison Li, Gibaidi M. Pharmacokinetics of digoxin in-the rat. Drug Metab Dispos 1976;4: Di Carlo FJ. Interspecies comparisons of oxisuran metabolism and pharmacokinetics. Drug Metab Rev 1979;10: Yacobi A, Kamath BL, Lai CM. Pharmacokinetics in chronic animal toxicity studies. Drug Metab Rev 1982;13: