Flecainide excretion in human breast milk
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1 Flecainide excretion in human breast milk Healthy human volunteers who intended not to breast feed were placed on a regimen of 100 mg oral flecainide every 12 hours for 51/2 days beginning 1 day after parturition. Milk and blood samples were collected during the dosing period and for 2 days after the last dose. Concentrations of flecainide in milk and plasma were assayed by HPLC. Apparent steady-state levels of flecainide in both milk and plasma were achieved in most cases by day 4 of the study. Highest daily average concentration of flecainide in milk ranged from 270 to 1529 ng/ml for the 11 subjects. Mean ± SD milk to plasma flecainide ratios were 3.7 ± 3.5, 3.2 ± 2.3, 3.5 ± 2.1, and 2.6 ± 0.7 on study days 2, 3, 4, and 5, respectively. After the last dose of flecainide, peak milk levels of the drug occurred at 3 to 6 hours and then declined monoexponentially. The half-life for elimination of flecainide from milk was 14.7 ± 3.5 hours and is very similar to the plasma elimination half-life of &canticle in healthy human subjects. The mean milk to plasma ratios for flecainide after the last dose were 2.3 ± 1.0 and 2.9 ± 1.1 at 24 and 48 hours after the dose, respectively. Based on the pharmacokinetics of flecainide in infants, the expected average steadystate plasma concentration of &canticle in a newborn infant consuming all of the milk production of its mother (-700 ml/day) would not be expected to exceed about 62 ng/tnl. Because previous studies in infants and children has indicated very few toxic side effects attributed to flecainide at plasma levels ranging from 100 to 990 ng/ml, it appears that the risk to a suckling infant of ingesting toxic amounts of flecainide in human breast milk is very low. (QIN PHARMACOL THER 1990;48:262-7.) Roy L. McQuimi, PhD, Alison Pisani, SRN, SCM, Samir Wafa, PhD, Shaw F. Chang, MS, Aldora M. Miller, BS, Jonathan M. Frappe% MRCOG, Geoffrey V. P. Chamberlain, FRCOG, and A. John Camm, FRCP, MD St. Paul, Minn., and London, England Many commonly used therapeutic drugs are known to be excreted in human breast milk.' For some of these drugs, particularly those that are weak organic bases, concentrations in milk may exceed by twofold or more those in plasma.' Thus the possibility of ingesting toxic amounts of a drug by a suckling infant is a real concern with some drugs. This concern is magnified in neonates because their ability to eliminate xenobiotics may be impaired as a result of immature metabolic and renal clearance systems. Flecainide acetate, a class Ic antiarrhythmic agent, is a lipophilic weak organic base (pka = 9.3) and thus may accumulate in human breast milk because of the ion trap effect. It is important to investigate the excretion of flecainide in human breast milk so that an assessment of the potential drug exposure to the suckling From 3M Pharmaceuticals, St. Paul, and St. George's Hospital Medical School, London. Received for publication Aug. 21, 1989; accepted June 1, Reprint requests: Roy L. McQuinn, PhD, 3M Pharmaceuticals, 3M Center, 270-3S-05, St. Paul, MN /1/ infant can be made. Accordingly, this study was designed to address this objective. METHODS This study was conducted in part at St. George's Hospital Medical School (London, England) under the direction of Professors A. J. Camm and G. V. P. Chamberlain and in part at the home of each subject. Institutional review board approval and informed patient consent were obtained before the study. Eleven healthy pregnant subjects between the ages of 17 and 32 years who had agreed not to breast feed their babies for the duration of this study completed the study. Study design. Before flecainide was administered, the health of each subject was assessed by physical examination, ECG, clinical laboratory tests, and history of drug therapy. During the morning of the first day after delivery (day 1), a sample of breast milk and an 8 ml aliquot of venous blood were collected just before the first dose of flecainide; milk samples were collected by use of a standard mechanical breast suction pump and blood was collected by venipuncture. Immediately after collection of predose milk and blood samples, oral
2 VOLUME 48 NUMBER 3 Flecainide in human milk 263 Table I. Subject demographics Subject No. Age (yr) Height (cm) Weight (kg) Date of delivery Daily flecainide dose (mg I kgl day) Mean ± SD 23.7 ± ± ± ± 0.4 Table II. Daily average milk and morning trough plasma levels (ng / ml) of flecainide during 5 days of oral dosing (100 mg every 12 hours) to healthy mothers who had just given birth Subject No. NS, No sample. Day] Day 2 Day 3 Day 4 Day 5 Milk Plasma Milk Plasma Milk Plasma milk Plasma Milk Plasma < NS NS NS NS NS NS NS flecainide was initiated at a dose of 100 mg every 12 hours and was continued for 51/2 days. Thus the first flecainide dose was given at approximately 10 AM on day 1 and the last dose was given at 10 AM on day 6. After each morning dose of flecainide, milk was collected (all that could be expressed with the breast pump) every 3 to 4 hours for 24 hours to stimulate lactation and to mimic a normal feeding schedule; an aliquot (-25%) of each collection was retained and pooled until the next morning dose of flecainide, while the remainder of each collection was discarded. On day 6, milk collections were made at 10 AM ( just before the last dose of flecainide) and at 1, 4, 7, and 10 PM. On day 7, milk was collected at 10 AM and at 1, 4, 7, and 10 PM and on day 8, milk was collected at 10 AM only; the milk samples collected on days 6, 7, and 8 were not pooled and 10 ml aliquots were retained from each collection for later analysis of flecainide. All milk samples were stored frozen ( - 20 C) until the time of analysis. In addition to the predose blood sample, additional blood samples were also collected just before each morning dose of flecainide (trough) and at 10 AM on days 7 and 8. After centrifugation, plasma was separated from red blood cells and stored frozen ( - 20 C) until analysis. Dosing and the collection of milk and blood samples were done in the home of each subject. Bioanalytic methods. The analysis of flecainide in milk was performed by use of a minor modification of an existing HPLC assay.' Briefly, flecainide was extracted from milk with hexane and then the hexane extract was taken to dryness.' The residue was reconstituted in mobile phase and an aliquot was analyzed by HPLC. Extraction efficiency of flecainide from co-
3 264 McQuinn et al. CLIN PHARMACOL THER SEPTEMBER 1990 Table III. Ratio of average daily flecainide concentration in milk to the next day morning trough plasma flecainide concentration Subject No. Day 1 Day 2 Day 3 Day 4 Day ND ND ND ND 6.6 ND ND ND ND ND Mean ± SD 1.9 ± ± ± ± ± 0.7 ND, Not determined. lostrum and milk is similar to that from plasma. Plasma levels of flecainide were determined according to the above HPLC method.' RESULTS Subject demographics are summarized in Table I. The mean ± SD age and postdelivery weight for the 11 subjects who completed the study are 23.7 ± 4.6 years and 64.3 ± 11.5 kg, respectively. The mean daily dose of flecainide was 3.2 ± 0.4 mg /kg. The concentrations of flecainide in milk during the 5 days of oral dosing every 12 hours represent average levels during 24-hour intervals beginning with the first dose of the drug. These daily average milk concentrations and daily morning trough plasma levels of flecainide are given in Table II. Apparent steady-state levels of flecainide in milk were achieved in most subjects by study day 4 (levels in milk of patients 1 and 8 were still increasing on day 5); apparent steady-state plasma flecainide levels were also achieved during the same time interval. There was no obvious or consistent lag between the times to achieve apparent steady-state milk and plasma concentrations. The individual highest daily average concentration of flecainide in milk ranged from 270 ng / ml (subject 9) to 1521 ng / ml (subject 1) during the 5 days of dosing every 12 hours. The very low levels of flecainide in milk and plasma from subject 9 are not readily explainable; noncompliance was not evident. The ratio of daily average milk flecainide levels to morning trough plasma levels measured at the end of the milk collection interval are listed in Table III. Within a given subject, the milk to plasma ratio changed very little during the 5-day dosing period. Also, with the exception of subject 9, the milk to plasma ratios of flecainide levels were very similar among subjects; mean ratios for the 11 subjects who completed the study were 3.7 ± 3.5, 3.2 ± 2.3, 3.5 ± 2.1, and 2.6 at. 0.7 on days 2, 3, 4, and 5, respectively. Milk samples collected just before the last dose of flecainide (Am, day 6) and at sequential intervals after the dose were analyzed individually for flecainide levels; plasma samples for flecainide analysis were collected just before the last dose and at 24 and 48 hours after the dose. Mean milk and plasma flecainide levels are depicted in Fig. 1. Highest measured levels of flecainide in milk (mean, 953 -± 529 ng/ ml) after the last dose usually occurred at 3 or 6 hours after the dose (9 of 11 subjects; Table IV). After the peak milk flecainide level was attained, milk flecainide levels appeared to decline monoexponentially. The terminal portion of the log milk concentration versus time data for each subject, when possible, was analyzed by linear regression, and half-life (42) values for the elimination of flecainide from milk were calculated. The ti,2 values (Table IV) ranged from 9.2 to 18.8 hours, with a mean of 14.7 ± 3.5 hours. The ratios of flecainide concentrations in milk to those in plasma during the washout phase were determined for each subject (Table V). No appreciable or consistent changes in the milk/plasma ratios were apparent during the 48 hours after the last dose. Mean ratios just before the last dose and at 24 and 48 hours after the dose were 2.6 ± 1.0, 2.3 -± 1.0, and 2.9 ± 1.1, respectively. DISCUSSION Subject daily average milk concentrations and morning trough plasma concentrations of flecainide on days 3, 4, and 5 were compared by linear regression analysis.
4 VOLUME 48 NUNMER3 Flecainide in human milk : : Z NM J iiiiiii iiiiiii 11 ii TIME AFTER LAST DOSE 0.0 Fig. 1. Mean ± SD concentrations of flecainide in human breast milk (circles) and plasma (triangles) after the last dose of a 51/2-day course of 100 mg oral flecainide acetate administered every 12 hours. The r2 value was 0.88, suggesting a good correlation between milk and plasma flecainide levels. The daily average concentration of flecainide in milk (Cm) was related to trough plasma concentration at steady-state (Cp) by the following equation: = 2.67 x The concentrations of flecainide in milk (Cm) and plasma (Cr) taken just before the last dose and at 24 and 48 hours after the dose were also compared by linear regression analysis. The resulting relationship (r2 = 0.88) was expressed as follows: Cm = 2.50 x CF Thus the relationship between milk and plasma levels of flecainide under steady-state and nonsteady-state conditions appears to be essentially the same. Overall, the concentration of flecainide in milk at any given time is approximately 2.5-fold greater than the corresponding concentration in plasma for most of these subjects. This apparent stable relationship between milk and plasma concentrations of flecainide is important because the milk samples were obtained during a period when milk composition was rapidly changing (decreasing protein content and increasing total lipid content). In light of this observation, it seems probable that the concentration of flecainide in mature milk (>1 month postpartum) relative to plasma concentration will not
5 266 McQuinn et al. CLIN PHARMACOL THER SEPTEMBER 1990 Table IV. Pharmacokinetic characteristics of flecainide in human breast milk after the last dose of a 51/2-day regimen of oral flecainide acetate (100 mg every 12 hours) Pharmacokinetic variable Subject No (hr) ND 6 Cm (ng/ ml) ND ND ND k (hr-1) ND ND (11r) ND 9.2 ND 18.8 ND, Not determined; tm time to maximum concentration; Cmax, maximum concentration; r2, correlation coefficient for the terminal log linear portion of the milk concentration versus time plot; k, elimination rate constant of flecainide from milk; 42, half-life for elimination of flecainide from milk. Table V. Ratio of flecainide concentration in milk to flecainide concentration in plasma* Subject No. Time after last dose (hr) Mean -± SD ND ND ± ND ± ND ND ND ± 1.1 ND, Not determined. *Milk and plasma samples were collected simultaneously just before the last dose of flecainide and at 24 and 48 hours after the dose. be appreciably different from that observed in this study (milk collected during the first week postpartum). The mean ti,2 for elimination of flecainide from milk was 14.7 ± 3.5 hours (Table IV). Although too few plasma samples were obtained for a direct estimation of plasma elimination ti,2 for these subjects, the previously reported plasma elimination t2 of 13 hours in healthy subjects' agrees very well with the milk elimination t1/2 determined in these subjects. Thus, once flecainide dosage is terminated, concentrations of flecainide in milk would be expected to decline at approximately the same proportional rate as plasma levels. In this study, the highest measured daily average concentration of flecainide in milk with a dosing regimen of 100 mg every 12 hours was 1529 ng/ ml (subject 1, day 5; Table II). If one assumes that an average of 700 ml of milk per day is expressed2 and that all the milk is consumed by an infant, then the daily oral dose to the infant at the above concentration in milk would be 1.07 mg flecainide. In a newborn infant of normal size, body weight of 4 kg and body surface area of 0.25 m2, this translates into a daily dose of 0.27 mg/kg or 4.28 mg /m2. The average plasma concentration of a drug at steady-state (C) can be estimated by the following expression: C = F x Dose/CL, X T in which F is the bioavailability, CL,, is the plasma clearance, and 1- is the dosing interval. The CL, for flecainide after oral dosage to children younger than 1 year of age and between 1 and 12 years of age has been reported to be approximately 10 and 16 ml/ min/kg, respectively.' After intravenous dosing with flecainide (2 mg /kg) to 14 children ranging in age from 7 days to 17 years (6 of the 14 children were 3 months of age or less), CLp for flecainide ranged from 3.0 to 48.2 ml/ min/kg, with a median value of 7.2 ml/ min/kg.7 If one uses the slower value for CLp (3 ml/ min/kg), assumes complete bioavailability (F = 1) of flecainide from the ingested milk, and assumes that approximately the same amount of drug is ingested over each 24-hour interval, then the estimated C for the hypothesized normal-sized infant would be approximately 62 ng /ml. Perry et al.' have reported that the trough plasma levels of flecainide in 63 patients who were being treated for a variety of arrhythmias and whose mean age was 8 years (13 patients were months) ranged from 100 to 990 ng / ml (mean, 360 ng/ ml); very few toxic side effects attributed to flecainide were observed in this previously reported pediatric study. In adults, the frequency of toxic side effects begins to increase appreciably at plasma levels exceeding 1000 ng /m1.8 Thus, based on the much higher plasma levels of
6 VOLUME 48 NUMBER 3 Flecainide in human milk 267 flecainide associated with usual therapeutic doses for flecainide (50 to 200 mg every 12 hours),5 it appears that the risk to a suckling infant of ingesting toxic amounts of flecainide in breast milk is very low. The identities of the major metabolites of flecainide in humans have been previously reported.' In general, they are less lipid than flecainide, are present in plasma in relatively low concentrations,' " and have been reported to have much less electrophysiologic effect on the canine heart than does flecainide itself.' Thus excretion of flecainide metabolites in milk is likely to be less extensive than flecainide itself and, in any case, is less likely to be of concern because of the much lower pharmacologic potency of the metabolites. References Subject No Mean ± SD ± ± ± ± 3.5 Findlay JWA. The distribution of some commonly used drugs in human breast milk. Drug Metab Rev 1983; 14: Wilson JT, Brown RD, Cherek DR, et al. Drug excretion in human breast milk. Clin Phannacokinet 1980;5:1-66. Chang SF, Miller AM, Fox JM, Welscher TM. Application of a bonded-phase extraction column for rapid sample preparation of flecainide from human plasma for high-performance liquid chromatographic analysisfluorescence or ultraviolet detection. Therap Drug Monit 1984;6: Chang SF, Miller AM, Fox JM, Welscher TM. Determination of flecainide in human plasma by high performance liquid chromatography with fluorescence detection. J Liquid Chromatogr 1984;7: Conard GJ, Ober RE. Metabolism of flecainide. Am J Cardiol 1984;53:41B-51B. Perry JC, McQuinn RL, Smith RT, Gothing C, Fredell P. Garson A. Flecainide acetate for resitant arrhythmias in the young: efficacy and phannacokinetics. J Am Coll Cardiol 1989;14: Till JA, Shineboume EA, Rowland E, et al. Pediatric use of flecainide in supraventricular tachycardia: clinical efficacy and phannacokinetics. Br Heart J 1989;62: Gentzkow GD, Sullivan JY. Extracardiac adverse effects of flecainide. Am J Cardiol 1984;53:101B-105B. McQuinn RL, Quarfoth GJ, Johnson JD, et al. Biotransformation and elimination of "C-flecainide acetate in humans. Drug Metab Dispos 1984;12: Chang SF, Welscher TM, Miller AM, McQuinn RL, Fox JM. High-performance liquid chromatographic method for the quantitation of a meta-o-dealkylated metabolite of flecainide acetate, a new antiarrhythmic. J Chromatogr Biomed Appl 1985;343: Welscher TM, McQuinn RL, Chang SF. A highperformance liquid chromatographic procedure with fluorescence detection for the meta-o-dealkylated lactam metabolite of flecainide acetate in human plasma. J Chromatogr Biomed Appl 1988;431: Guehler J, Gomick CC, Tobler HG, et al. Electrophysiologic effects of flecainide and its major metabolites in the canine heart. Am J Cardiol 1985;55:
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