Flecainide pharmacokinetics in healthy volunteers: the influence of urinary ph

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1 Br. J. clin. Pharmac. (1985), 20, Flecainide pharmacokinetics in healthy volunteers: the influence of urinary ph A. JOHNSTON, S. WARRNGTON' & P. TURNER Department of Clinical Pharmacology, St Bartholomew's Hospital, London, ECA 7BE and 1Charterhouse Clinical Research Unit, Boundary House, Charterhouse Street, London, EClM 6HR, UK 1 The pharmacokinetics of a single 300 mg oral dose of flecainide were studied in eight healthy volunteers on four separate occasions under different conditions of urinary ph. 2 The urinary ph of the volunteers was manipulated chemically to produce four distinct groups spanning the range of urinary ph (ph 5-8). 3 Neither the rate nor extent of flecainide absorption was significantly affected by changes in urinary ph. 4 However the plasma elimination of flecainide was found to be inversely proportional to urinary ph and the volunteers' mean elimination half-life ranged between h (s.d.) at the extreme acid ph and 17.6 ± 6.3 h at the extreme alkali ph. 5 The urinary elimination and renal clearance of flecainide decreased with increasing urinary ph. 6 The influence of changes in urinary ph on the pharmacokinetics of flecainide will contribute to the normal variability in flecainide serum concentrations seen in patients and should be considered in patients who have adverse reactions to the drug at low dosage or who fail to respond at high doses. Keywords flecainide urinary ph pharmacokinetics ntroduction The pharmacokinetics of the antiarrhythmic agent flecainide have been shown to change substantially when urinary ph is altered from alkaline to acid; serum elimination half-life is decreased, the area under the concentrationtime curve (AUC) is reduced and the urinary excretion and renal clearance of the drug increased at low urinary ph (Muhiddin et al., 1984). These changes are seen at extremes of urinary ph but it is important to know if the alterations are gradual throughout the range of urinary ph or if the changes occur abruptly at a threshold value of urinary ph. We have studied the pharmacokinetics of flecainide in normal volunteers at four different urinary ph values, the extremes and two intermediate values, to quantify the variation in pharmacokinetics with changes in ph. Methods The subjects were eight healthy adults, four male, aged between years and weighing kg. They were asked to take no drugs from 1 week before until the end of the study. After an overnight fast each was given a single oral dose of flecainide acetate 300 mg on four occasions 1 week apart. On each occasion the subject's urinary ph was modified by one of four Correspondence: Mr A. Johnston, Department of Clinical Pharmacology, St Bartholomew's Hospital, London EClA 7BE 333

2 334 A. Johnston, S. Warrington & P. Turner treatments started 21 h before and continued for 48 h after drug administration: (A) 0.5 g ammonium chloride taken every 3 h, and 1 g before sleep. (B) 0.25 g ammonium chloride taken every 3 h, and 0.5 g before sleep. (C) No treatment. (D) 2 g sodium bicarbonate every 4 h. The order of treatment was open, balanced and the subjects were randomly allocated to the treatment orders. Blood samples (5 ml) were taken from an indwelling venous catheter just before each dose of flecainide and at 30 and 45 min, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 32 and 48 h afterwards. The volunteers were asked to empty their bladders before receiving the drug and all urine was collected from 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-24,24-32 and h. The ph and volume of urine were measured immediately following each collection to minimise ph changes occurring on storage. To maintain urine production during the first 12 h the subjects drank at least 100 ml water each hour. The serum samples and aliquots of the urine samples were stored at -20 C until analysed for flecainide using a specific gas chromatographic method (Johnson et al., 1984). The pharmacokinetic parameters were calculated from the plasma concentration-time data using the interactive computer program STRPE (Johnston & Woollard, 1983). Mean residence time (MRT) was calculated as the ratio of [area under the curve of a plot of the product of concentration and time against time (AUMC)] and [area under the concentration vs time curve (AUC)]. Both AUC and AUMC were calculated using the trapezoidal method and extrapolated to infinity using the terminal phase rate constant (Xi) and the last measured serum concentration (Gibaldi & Perrier, 1982). The total urinary excretion of flecainide was estimated using the non-linear curve fitting program SMP (Johnston, 1985) to calculate, from the urine data, the asymptotic cumulative urinary excretion of the drug at infinite time. The equation used was: C = UOO (1 -e k(t- lag time)) where C is the cumulative urinary excretion at time t, k the urinary elimination rate constant and U,O the asymptotic cumulative excretion at infinite time. The renal clearance of flecainide was calculated as the ratio of Uo, to AUC (Tucker, 1981). Statistical comparisons of the treatment groups was by Friedman's non-parametric analysis of variance and the correlation of cumulative urinary excretion of flecainide with urinary ph was carried out using Spearman's rank correlation. The study protocol was approved by the Hospital Ethics Committee. Results Urinary ph The four urinary ph treatments successfully maintained the mean urinary ph of each group within the ranges, (A) , (B) , (C) and (D) The changes in mean urinary ph of each group with time can be seen in Figure 1. The individual mean urinary phs for the subjects during each treatment are shown in Figure 4. The differences between treatments were significant (P < 0.01). Plasma pharmacokinetics The mean plasma concentration-time profile for each treatment is displayed in Figure 2. There were no significant differences between treatments with respect to the absorption half-life, lag time, Cmax, tmax or volume of distribution of flecainide. These data are shown graphically in Figure 3. The elimination half-life, AUC and MRT of flecainide increased with increasing urinary ph (Figure 4) and the differences between treatments for these parameters were significant (P < 0.01). Urinary excretion The cumulative urinary excretion of flecainide decreased significantly (Figure 5) with increasing urinary ph (r, = -0.46, P < 0.01) but the differences between treatments failed to reach statistical significance (0.1 > P > 0.05) owing to individuals failing to show consistent changes across the treatments, e.g. subject 5 in Table 1. The renal clearance of flecainide (Table 1) also decreased with increasing urinary ph and there were significant differences between the treatments (P < 0.01). Discussion The changes in flecainide pharmacokinetics at extremes of urinary ph seen in a previous study (Muhiddin et al., 1984) have been confirmed. The changes appear to be linearly related to

3 Flecainide: the influence of urinary ph C 7 0- / \..'' "8.," "st,'w'*''-'-- c) %t.,. t 0 t. * v Al- B A a g Time (h),,.., *, is * Figure 1 The volunteers' mean urinary ph during the four treatments, A ammonium chloride high dose, B ammonium chloride low dose, C no treatment and D sodium bicarbonate. urinary ph over the range studied, which was wide (ph 5-8). The mean increase in AUC from acid (group A) to basic (group D) urinary ph represented a change of 58%; this would cause an increase of the same magnitude in the average concentration at steady state. However the more clinically relevant comparisons would be between group C (unmodified urinary ph) and groups A and D, where the changes in AUC are -30% and +9% respectively. However since the inter-subject variation in AUC at unmodified urinary ph is high (coefficient of variation 37%) the intrasubject variations are comparatively less important in determining flecainide serum levels _ - ~~~% A. XD 400- c co.(? ~200 CL B A Time (h) Figure 2 The mean plasma concentration-time profile for flecainide during each treatment, A ammonium chloride high dose, B ammonium chloride low dose, C no treatment and D sodium bicarbonate.

4 336 A. Johnston, S. Warrington & P. Turner Absorption half-life (min) Lag time (min) Cmax (n t1) tmm (h) V4 d $#in) ).(1) A B C D A B C D A B C D A B C D A B C D Figure 3 The individual changes in the subjects' absorption half-life, lag time, Cm,:, t,m,, and Vd (area) during the four urinary ph treatments (A ammonium chloride high dose, B ammonium chloride low dose, C no treatment and D sodium bicarbonate). 0-0 mean value.

5 Eliminadon helf4. (h) (mg 1- h) Flecainide: the influence of urinary ph Y. U;in ry ph is a.6 A 8 C D * K- K a.-m An 9 C D5.. v s a a 9.A B C D A B C D F S.0 p. A B C- D Figure 4 The individual changes in the subjects elimination half life, AUC, MRT and urinary ph during each treatment (A ammonium chloride high dose, B ammonium chloride low dose, C no treatment and D sodium bicarbonate). 0-0 mean value. 140 A 120 E x w 'a.e c) a) LL Time (h) Figure 5 The mean cumulative urinary excretion of flecainide during each treatment period (A ammonium chloride high dose, B ammonium chloride low dose, C no treatment and D sodium bicarbonate).

6 338 A. Johnston, S. Warrington & P. Turner Table 1 Renal excretion and renal clearance of flecainide during the four different urinary phs (A,B,C,D) Renal excretion (mg) Renal clearance (ml min-') Subjects A B C D A B C D Mean s.d The influence of changes in urinary ph on the pharmacokinetics of flecainide will contribute to the variability in flecainide serum concentrations seen in patients and should be considered in the case of individuals who have adverse reactions to the drug at low dosage or who fail to respond at high doses or if a patient's urinary ph undergoes pathological change, e.g. metabolic acidosis. We thank Riker Laboratories for financial support and arranging the analysis of the samples at Huntingdon Research Centre. References Gibaldi, M. & Perrier, D. (1982). Noncompartmental analysis based on statistical moment theory. n Pharmacokinetics, 2nd Edition Chapter 11, New York: Marcel Dekker. Johnson, J. D., Carlson, G. L., Fox, J. M., Millar, A. M., Chang, S. F. & Conard, G. J. (1984). Quantitation of flecainide acetate, a new antiarrhythmic agent, in biological fluids by gas chromatography with electron capture detection. J. pharm. Sci., 73, Johnston, A. &Wollard, R. C. (1983). STRPE: An interactive computer program for the analysis of drug pharmacokinetics. J. pharmac. Methods, 9, 193. Johnston, A. 1985). SMP: a computer program in BASC for non linear curve fitting. J. pharmac. Methods, (in press). Muhiddin, K. A., Johnston, A. & Turner, P. (1984). The influence of urinary ph on flecainide excretion and its serum pharmacokinetics. Br. J. clin. Pharmac., 17, Tucker, G. T. (1981). Measurement of the renal clearance of drugs. Br. J. clin. Pharmac., 12, (Received 14 February 1985, accepted 16 May 1985)