Eur J Clin Pharmacol (1991) 40:629-630 European J . . . . ,of ( ~ [ ~ ( ~
003169709100144C
© Springer-Verlag 1991
Comparison of the bioavailability of two slow release preparations of disopyramide M. G. Bogaert, F. Belpaire, G. De Wilde, and R. A. Lefebvre Heymans Institute of Pharmacology, University of Gent Medical School, Gent, Belgium Received: April 11, 1990/Accepted in revised form: September 3, 1990
Summary, The bioavailability of two slow release preparations of disopyramide has been compared in a randomized cross-over trial of Rythmodan L.A. 250 mg b.d. and Dirytmin Durettes 300 mg b.d., given to 10 healthy volunteers. The plasma concentrations of disopyramide were measured on the 5th day of each treatment period. With both preparations, plasma concentrations were well sustained. The amount absorbed was slightly lower after Rythmodan L. A. than after Dirytmin Durettes, but the fluctuations over a dosing interval were significantly more pronounced for Dirytmin Durettes than for Rythmodan L. A.
amide over the 12 h dosing interval. A standard breakfast and lunch were provided 2 h and 6 h, respectively, after administration. The products used were commercially available (Rythmodan L. A., manufacturing date 88L12, and Dirytmin Durettes manufacturing date 88H30). Racemic disopyramide was determined by H P L C with UV-detection, using parachlorodisopyramide as the internal standard. Between-run coefficients of variation were 9.9% (n = 7) and 5.1% (n = 7), using plasma samples spiked with 2 and 4 gg/ml respectively, and the accuracy was 98.4% and 99.9% respectively. Comparison of the A U C , Cm~, Cminand Cmax/Cmin ratio was done using Westlake's modification of A N O V A based confidence intervals [2]. Values within the 8(~120% range were considered to signify bioequivalence.
Key words: Disopyramide, slow release, plasma concentrations, bioavailability
Disopyramide is a frequently used antiarrhythmic. Its therapeutic plasma concentration is considered to be in the range 2 to 7.5 gg/ml [1], and in order to maintain that level, it is most often administered twice daily as an oral slow release preparation. Two such preparations are marketed in Belgium: Rythmodan L.A., 250 mg (Roussel) and Dirytmin Durettes, 150 mg (Astra); both contain a racemic mixture. In order to compare their bioavailability, disopyramide concentrations in plasma over a dosing interval were measured during steady state.
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Methods Ten volunteers, 4 m and 6 f, aged 24-33 y, gave written informed consent to participation in the study, which was approved by the Medical Ethics Committee of the University Hospital. The volunteers were in good health, as judged by history, physical examination, E C G and biochemistry; they did not take any drugs. The volunteers took part in a cross-over randomized trial of Rythmodan L.A. 250 mg twice daily, or Dirytmin Durettes 2 x 150 mg twice daily, each for 5 days, with an interval of 2 days. On the 5th day of each treatment period, after an overnight fast, each volunteer took the morning dose with 100 ml water, and blood was sampled at regular intervals for determination of the plasma concentrations of disopyr-
I
2
j
L
j
6 Time (h)
i
8
110
12
Fig. 1. Plasma disopyramide concentrations during a 12 h dosing interval on the 5th day of treatment with either Rythmodan L.A. 250 mg b. d. (o--o) or Dirytmin Durettes 2 x 150 mg b. d. (/x - - - A ,) administered in a cross-over randomized sequence. Mean ( + SEM) for the 10 volunteers.
M. G. Bogaert et al.: Disopyramide availability
630
Table 1. Pharmacokineticparameters
Rythmodan L.A. Volunteer 1 2 3 4 5 6 7 8 9 10 Mean (SEM) Dirytmin durettes Volunteer 1 2 3 4 5 6 7 8 9 10 Mean (SEM) 95% C.I.
Cmin
Cmax
(gg/ml)
(gg/ml)
Cmax/Cmi n
AUC
2.13 1.89 0.40 1.05 3.07 1.90 2.91 2.12 1.71 1.80 1.90 (0.25)
3.36 2.84 2.45 2.30 4.59 3.23 5.76 3.61 2.82 2.95 3.39 (0.33)
1.58 1.50 6.18 2.19 1.50 1.70 1.98 1.70 1.65 1.64 2.16 (0.45)
32.24 28.98 19.46 19.77 45.70 33.11 49.20 34.67 27.92 29.88 32.10 (3.03)
1.49 1.60 1.35 1.21 1.67 2.23 2.39 1.55 1.73 1.97 1.72 (0.12) 69-131
4.66 3.50 4.71 3.71 4.59 4.02 6.13 3.78 3.82 3.57 4.25 (0.25) 63-137
3.13 2.19 3.49 3.07 2.75 1.80 2.56 2.44 2.21 1.81 2.54 (0.18) 49-151
36.97 29.94 32.00 28.41 36.59 36.54 48.05 33.58 33.19 33.88 34.91 (1.71) 80-120
(gg. h. ml- 1)
Minimal (C-nm)and maximal (Cmax) plasma concentrations, ratio between maximal and minimal plasma concentrations over a dosing interval (CmJCmi,), and area under the plasma concentration time curve (AUC), on the 5th day of Rythmodan L. A; (2 x 250 mg) and Dirytmin Durettes (2 x 300 rag) treatment. Individual values and means with SEM are given. Calculations of the confidence intervals (C. I.) according to Westlake, based on the ratio between results with Dirytmin Durettes and Rythmodan L.A. in each volunteer for each of the parameters, are also given. The 95% confidence intervals are expressed as percentage of the mean value.
Results and discussion B o t h preparations were well tolerated. P e a k plasma concentrations after both preparations were o b t a i n e d at 3 or 4 h, except for one volunteer on R y t h m o d a n (6 h). In n o n e of the volunteers was a p e a k concentration above 7 . 5 m g . m 1 - 1 found; the concentrations were below 2 gg. ml-1 for part of the time in 6 of the volunteers on R y t h m o d a n , and in 8 of the volunteers on Dirytmin. T h e results are in a g r e e m e n t with o t h e r data a b o u t slow release disopyramide formulations (see e. g. 3-5). T h e average plasma concentrations over one dosing interval for the two products are shown in Fig. 1. T h e phar-
macokinetic parameters and their statistical evaluation are given in Table 1. T h e average plasma concentrations at m o s t sampling points were higher for Dirytmin, and the area u n d e r the curve was slightly but not significantly higher for D i r y t m i n (at a daily dose of 600 mg) t h a n for R y t h m o d a n (daily dose 500 rag). W h e n the areas u n d e r the curve were normalized for the dose given, the ratio R y t h m o d a n L. A.-Dirythmin durettes averaged 1.09 (confidence intervals 0.94 and 1.24). It is k n o w n that disopyramide exhibits non-linear protein binding and elimination kinetics of the unb o u n d fraction. This does not invalidate the c o m p a r i s o n of the A U C s , but the calculated F-value does not accurately represent bioavailability. F r o m the Fig. and f r o m the Table it is a p p a r e n t that the fluctuation over the dosing interval (Cmax/Cmin) w a s significantly m o r e p r o n o u n c e d after D i r y t m i n (Crnax/Cmin: 2.54 + 0.18) than after R y t h m o d a n (Cm,x/C,~,: 2.16 + 0.45). With R y t h m o d a n , Cmax/Cmin ranged f r o m 1.50 to 2.19 in 9 of the 10 volunteers, but in one volunteer, the Cmax/Cminvalue was 6.13, due to an unexpectedly low trough c o n c e n t r a t i o n (0.4 gg/ml). W h e t h e r the low concentration was due to n o n - c o m p l i a n c e could not be ascertained. F o r D i r y t m i n Durettes, the Cmax/Cminratio r a n g e d f r o m 1.80 to 3.49. It can be concluded that when the a m o u n t a b s o r b e d of b o t h preparations was similar, fluctuation over a dosing interval was less important for R y t h m o d a n L . A . than for D i r y t m i n Durettes, which is an advantage for chronic use of this preparation.
Acknowledgements. The study was financially supported by Roussel Belgium. Dr. R. A. Lefebvre is a Senior Research Associate of the National Fund for Scientific Research.
References 1. Benet LZ, Massoud N, Gambertoglio JG (1984) Pharmacokinetic basis for drug treatment. Raven Press, New York, p. 428 2. Westlake WJ (1972) Use of confidence intervals in analysis of comparative bioavailability trials. J Pharm Sci 61:1340-1341 3. Torstensson I, Hofvendahl S (1982) Steady-state pharmacokinetics of two formulations and dosage regimes of oral disopyramide. Curr Ther Res 31:617-624 4. Capparelli EV, DiPersio DM, Zhao H, Kluger J, Chow MSS (1988) Clinical pharmacokinetics of controlled-release disopyramide in patients with cardiac arrhythmias. J Clin Pharmacol 28: 306-311 5. Lien E, Bakke OM (1983) Sustained release disopyramide compared to plain capsules after change-over from intravenous infusion. Br J Clin Pharmaco116: 71-76 Prof. Dr. M.Bogaert Heymans Institute of Pharmacology University of Gent Medical School De Pintelaan 185 B-9000 Gent Belgium
003169709100144C
© Springer-Verlag 1991
Comparison of the bioavailability of two slow release preparations of disopyramide M. G. Bogaert, F. Belpaire, G. De Wilde, and R. A. Lefebvre Heymans Institute of Pharmacology, University of Gent Medical School, Gent, Belgium Received: April 11, 1990/Accepted in revised form: September 3, 1990
Summary, The bioavailability of two slow release preparations of disopyramide has been compared in a randomized cross-over trial of Rythmodan L.A. 250 mg b.d. and Dirytmin Durettes 300 mg b.d., given to 10 healthy volunteers. The plasma concentrations of disopyramide were measured on the 5th day of each treatment period. With both preparations, plasma concentrations were well sustained. The amount absorbed was slightly lower after Rythmodan L. A. than after Dirytmin Durettes, but the fluctuations over a dosing interval were significantly more pronounced for Dirytmin Durettes than for Rythmodan L. A.
amide over the 12 h dosing interval. A standard breakfast and lunch were provided 2 h and 6 h, respectively, after administration. The products used were commercially available (Rythmodan L. A., manufacturing date 88L12, and Dirytmin Durettes manufacturing date 88H30). Racemic disopyramide was determined by H P L C with UV-detection, using parachlorodisopyramide as the internal standard. Between-run coefficients of variation were 9.9% (n = 7) and 5.1% (n = 7), using plasma samples spiked with 2 and 4 gg/ml respectively, and the accuracy was 98.4% and 99.9% respectively. Comparison of the A U C , Cm~, Cminand Cmax/Cmin ratio was done using Westlake's modification of A N O V A based confidence intervals [2]. Values within the 8(~120% range were considered to signify bioequivalence.
Key words: Disopyramide, slow release, plasma concentrations, bioavailability
Disopyramide is a frequently used antiarrhythmic. Its therapeutic plasma concentration is considered to be in the range 2 to 7.5 gg/ml [1], and in order to maintain that level, it is most often administered twice daily as an oral slow release preparation. Two such preparations are marketed in Belgium: Rythmodan L.A., 250 mg (Roussel) and Dirytmin Durettes, 150 mg (Astra); both contain a racemic mixture. In order to compare their bioavailability, disopyramide concentrations in plasma over a dosing interval were measured during steady state.
/
\
/
\
/
\
/
\
'
o~
o O c c
o 2¸ o
E
m o
Methods Ten volunteers, 4 m and 6 f, aged 24-33 y, gave written informed consent to participation in the study, which was approved by the Medical Ethics Committee of the University Hospital. The volunteers were in good health, as judged by history, physical examination, E C G and biochemistry; they did not take any drugs. The volunteers took part in a cross-over randomized trial of Rythmodan L.A. 250 mg twice daily, or Dirytmin Durettes 2 x 150 mg twice daily, each for 5 days, with an interval of 2 days. On the 5th day of each treatment period, after an overnight fast, each volunteer took the morning dose with 100 ml water, and blood was sampled at regular intervals for determination of the plasma concentrations of disopyr-
I
2
j
L
j
6 Time (h)
i
8
110
12
Fig. 1. Plasma disopyramide concentrations during a 12 h dosing interval on the 5th day of treatment with either Rythmodan L.A. 250 mg b. d. (o--o) or Dirytmin Durettes 2 x 150 mg b. d. (/x - - - A ,) administered in a cross-over randomized sequence. Mean ( + SEM) for the 10 volunteers.
M. G. Bogaert et al.: Disopyramide availability
630
Table 1. Pharmacokineticparameters
Rythmodan L.A. Volunteer 1 2 3 4 5 6 7 8 9 10 Mean (SEM) Dirytmin durettes Volunteer 1 2 3 4 5 6 7 8 9 10 Mean (SEM) 95% C.I.
Cmin
Cmax
(gg/ml)
(gg/ml)
Cmax/Cmi n
AUC
2.13 1.89 0.40 1.05 3.07 1.90 2.91 2.12 1.71 1.80 1.90 (0.25)
3.36 2.84 2.45 2.30 4.59 3.23 5.76 3.61 2.82 2.95 3.39 (0.33)
1.58 1.50 6.18 2.19 1.50 1.70 1.98 1.70 1.65 1.64 2.16 (0.45)
32.24 28.98 19.46 19.77 45.70 33.11 49.20 34.67 27.92 29.88 32.10 (3.03)
1.49 1.60 1.35 1.21 1.67 2.23 2.39 1.55 1.73 1.97 1.72 (0.12) 69-131
4.66 3.50 4.71 3.71 4.59 4.02 6.13 3.78 3.82 3.57 4.25 (0.25) 63-137
3.13 2.19 3.49 3.07 2.75 1.80 2.56 2.44 2.21 1.81 2.54 (0.18) 49-151
36.97 29.94 32.00 28.41 36.59 36.54 48.05 33.58 33.19 33.88 34.91 (1.71) 80-120
(gg. h. ml- 1)
Minimal (C-nm)and maximal (Cmax) plasma concentrations, ratio between maximal and minimal plasma concentrations over a dosing interval (CmJCmi,), and area under the plasma concentration time curve (AUC), on the 5th day of Rythmodan L. A; (2 x 250 mg) and Dirytmin Durettes (2 x 300 rag) treatment. Individual values and means with SEM are given. Calculations of the confidence intervals (C. I.) according to Westlake, based on the ratio between results with Dirytmin Durettes and Rythmodan L.A. in each volunteer for each of the parameters, are also given. The 95% confidence intervals are expressed as percentage of the mean value.
Results and discussion B o t h preparations were well tolerated. P e a k plasma concentrations after both preparations were o b t a i n e d at 3 or 4 h, except for one volunteer on R y t h m o d a n (6 h). In n o n e of the volunteers was a p e a k concentration above 7 . 5 m g . m 1 - 1 found; the concentrations were below 2 gg. ml-1 for part of the time in 6 of the volunteers on R y t h m o d a n , and in 8 of the volunteers on Dirytmin. T h e results are in a g r e e m e n t with o t h e r data a b o u t slow release disopyramide formulations (see e. g. 3-5). T h e average plasma concentrations over one dosing interval for the two products are shown in Fig. 1. T h e phar-
macokinetic parameters and their statistical evaluation are given in Table 1. T h e average plasma concentrations at m o s t sampling points were higher for Dirytmin, and the area u n d e r the curve was slightly but not significantly higher for D i r y t m i n (at a daily dose of 600 mg) t h a n for R y t h m o d a n (daily dose 500 rag). W h e n the areas u n d e r the curve were normalized for the dose given, the ratio R y t h m o d a n L. A.-Dirythmin durettes averaged 1.09 (confidence intervals 0.94 and 1.24). It is k n o w n that disopyramide exhibits non-linear protein binding and elimination kinetics of the unb o u n d fraction. This does not invalidate the c o m p a r i s o n of the A U C s , but the calculated F-value does not accurately represent bioavailability. F r o m the Fig. and f r o m the Table it is a p p a r e n t that the fluctuation over the dosing interval (Cmax/Cmin) w a s significantly m o r e p r o n o u n c e d after D i r y t m i n (Crnax/Cmin: 2.54 + 0.18) than after R y t h m o d a n (Cm,x/C,~,: 2.16 + 0.45). With R y t h m o d a n , Cmax/Cmin ranged f r o m 1.50 to 2.19 in 9 of the 10 volunteers, but in one volunteer, the Cmax/Cminvalue was 6.13, due to an unexpectedly low trough c o n c e n t r a t i o n (0.4 gg/ml). W h e t h e r the low concentration was due to n o n - c o m p l i a n c e could not be ascertained. F o r D i r y t m i n Durettes, the Cmax/Cminratio r a n g e d f r o m 1.80 to 3.49. It can be concluded that when the a m o u n t a b s o r b e d of b o t h preparations was similar, fluctuation over a dosing interval was less important for R y t h m o d a n L . A . than for D i r y t m i n Durettes, which is an advantage for chronic use of this preparation.
Acknowledgements. The study was financially supported by Roussel Belgium. Dr. R. A. Lefebvre is a Senior Research Associate of the National Fund for Scientific Research.
References 1. Benet LZ, Massoud N, Gambertoglio JG (1984) Pharmacokinetic basis for drug treatment. Raven Press, New York, p. 428 2. Westlake WJ (1972) Use of confidence intervals in analysis of comparative bioavailability trials. J Pharm Sci 61:1340-1341 3. Torstensson I, Hofvendahl S (1982) Steady-state pharmacokinetics of two formulations and dosage regimes of oral disopyramide. Curr Ther Res 31:617-624 4. Capparelli EV, DiPersio DM, Zhao H, Kluger J, Chow MSS (1988) Clinical pharmacokinetics of controlled-release disopyramide in patients with cardiac arrhythmias. J Clin Pharmacol 28: 306-311 5. Lien E, Bakke OM (1983) Sustained release disopyramide compared to plain capsules after change-over from intravenous infusion. Br J Clin Pharmaco116: 71-76 Prof. Dr. M.Bogaert Heymans Institute of Pharmacology University of Gent Medical School De Pintelaan 185 B-9000 Gent Belgium
