Br. J. clin. Pharmac. (1979), 8, 267-271
A PHARMACOKINETIC COMPARISON OF TWO SUSTAINED-RELEASE ORAL PROCAINAMIDE PREPARATIONS P. HORE, P. BONES, 'T. ROLLINSON & H. IKRAM Department of Cardiology, The Princess Margaret Hospital, Christchurch, New Zealand and ' Department of Biochemistry, Christchurch Public Hospital, Christchurch, New Zealand
1 The pharmacokinetics of two different sustained-release oral procainamide preparations were studied in ten hospital patients with normal blood ureas and no clinical evidence of heart failure. Each patient received either one or other preparation at 12 hourly intervals for four doses. Frequent blood sampling enabled close monitoring of blood levels. 2 Results showed that both preparations were essentially similar in their pharmacokinetics. Both effectively double the half-life of conventional oral procainamide to 6.5 h and are suitable as prophylactic preparations. One patient developed toxic levels, thought to be related to her metabolic status of being a very slow acetylator. To avoid toxicity pre-therapy assessment of a patient's cardiac and renal function and acetylator status is advised.
Introduction
Procainamide hydrochloride is a major antiarrhythmic drug which has been used in the treatment of both atrial and ventricular tachyarrhythmias for over 20 years. It is commonly used to prevent ventricular arrhythmias following myocardial infarction (Koch-Weser, Klein, Foo-Canto, Kastor & Desanctis, 1969; Giardina, Heissenbuttel & Bigger, 1973). Its use as a prophylactic agent has been severely restricted by the short half-life of 3.5 h (Koch-Weser & Klein, 1971) of the conventional oral preparation (Pronestyl, procainamide hydrochloride, Squibb). This has meant that 3 hourly administration of the drug has been necessary to maintain therapeutic plasma levels (Koch-Weser et al., 1969; Shaw, Kumana, Royds, Padgham & Hamer, 1974). To overcome this, sustained-release preparations have recently been developed. This study investigated the relative pharmacokinetics of two such preparations with differing slow release mechanisms. These were Procainamide Durules (Astra: Sweden) and Prokainamid Retard (Collett A/S: Norway). Methods
Procainamide Durules are composed of an insoluble matrix impregnated with 0.5 g procainamide hydrochloride. Prokainamid Retard consists of 0.5 g procainamide hydrochloride in the form of particles coated by a thermoplastic substance, which are
0306-5251/79/090267-05 $1.00
compacted into tablets and further coated by the thermoplastic substance. Ten patients were selected from the cardiology ward and randomly allotted to receive either one or other preparation. The individual dosage ranged from 25-32.5 mg/kg twice daily (Koch-Weser & Klein, 1971; Hansteen, Landmark, Fremstad, Dahl, Jacobsen, Marthinsen, Waaler, Frislid & Lunde, 1976). This amount was given at four 12-hourly intervals. There were six males and four females whose ages ranged from 35 years to 66 years with a mean of 55 years. The clinical details are summarized in Table 1. The patients who were selected fulfilled the following conditions: (i) normal blood urea; (ii) no clinical evidence of cardiac failure; (iii) no myocardial infarction in the previous 72 h. Using these criteria we hoped to avoid those factors known to adversely affect the normal pharmacokinetics of procainamide (Koch-Weser & Klein, 1971; Weily & Genton, 1972). Blood samples were taken at intervals varying from 30 min to 60 min for the first 5 h following each dose, then less frequently in the last 7 h of the 12 hourly cycle. The first dose was given at 19.00 h which was approximately 1.25 h after the evening meal, in all but two cases, when it was given at 07.00 h, approxi5 / 2 $ Macmillan Journals Ltd 1979
268
P. HORE, P. BONES, T. ROLLINSON & H. IKRAM
mately 1 h before breakfast. The samples were assayed by a fluorimetric method (Ambler & Masarei, 1976). The results were analysed for: (i) half-life (TI) (ii) time to peak plasma concentration (Tp) (iii) and (iv) the effect on T, and Tp of taking the drugs before or after meals (v) maximum plasma levels (vi) length of time above the therapeutic minimum (4 ig/ml) (vii) length of time in the potentially toxic range (8-16 jig/ml) (therapeutic and toxic ranges according to Koch-Weser & Klein, 1971).
doses. Her results were atypical as were those of Mrs E.W. and neither are included in the statistical results of Table 2 or the graphs of Figures 1 and 2. They require further explanation and are presented in detail in the Discussion. Table 2 is a summary of the results of the other eight patients. It shows that the pharmacokinetics of the two preparations are very similar. There was no statistically significant difference found between any of the results. Figure 1 shows the mean plasma levels plotted as a function of time for the 48-h period during which the trial was conducted. The first dose is seen to reach a lower maximum level than subsequent doses. For analysis of equilibrium conditions we took the third and fourth curves as being representative. In the equilibrium state Retard and Durules remained above the therapeutic minimum for 67% and 72% of the time respectively. The mean time recorded in the potentially toxic range was 1.2 h for both preparations.
Results
Of the ten patients selected, one did not complete the trial. Mrs D.P. on Durules developed severe toxic symptoms and the drug was stopped after three Table 1 Clinical data
Age (years)
Drug
Dose (mg/kg twice daily)
Mrs I.P. Mr L.C. Mr P.R. Mr L.F. Mrs D.P. Mr F.L.
35 59 49 57 66 59
R R D D D R
27.5 28.5 27.25 32.25 32.5 32.5
Mrs F.McK. Mr G.M. Mrs E.W. Mr R.M.
62 50 64 48
R R D D
30.0 28.5 31.0 26.5
Patient
Diagnosis
Myocardial infarction Chest pain Atrial fibrillation Angina Aortic incomp./controlled left-ventricular failure Hypertension/controlled left-ventricular failure/ aortic incompetence Angina/hypertension Chest pain Investigation of atrial fibrillation Chest pain
(R = Retard, D = Durules).
Table 2 Pharmacokinetic results of eight patients
Mean half-life, TI (h) Mean time-to-peak, Tp (h) Mean maximum levels (pg/mI) Dose I IV Mean time above therapeutic minimum (h) Dose III Dose IV Mean time in potentially toxic range for third and fourth doses (h)
Durules
Retard
t
P
5.9+0.8 2.6+0.5
6.9+1.0 2.0+0.4
1.74
2.18
NS NS
5.8 7.7 9.2 8.0
4.9 7.6 7.6 7.8
NS
7.8 8.2 1.2
8.0 9.2 1.2
NS NS NS NS
Range (0-3.8) Range (0-4.8)
PHARMACOKINETICS OF PROCAINAMIDE
...............................................
269
..................
......................
...............................................
............................................... ...............................................
.....................
................... ..................
............................................... ............................................
..................
.................
.............................................
...................................................
...................................... ..............................................
................ ...............
........................... ..
L .................... e _.................... ~~~~~~~~~~.. t 6 ..........................
__L
wJ ........................ 4*........................ .......................... ...........................
... ^t.......................... .
w.
.......... ...
....
....................... .
..
...
........................
........
...............
_........ ....
.....
...
.............. .
....
~~~~~~~~~~~. .......
---f... --------1....
.................. .. ..........
.
--
.
.
......
\
.....,j.....
..... ... ......
...
...
~~~~~~~~~~~~~.
._.. . .. .. ..
..
................,-
. . ............... .. .\. .
.........
........
. ., ----------.......... ,....... ...... .
....... ................
...........
. s._....
........... ........ .... .... . ... §{^\.......
48.
....
......
*...-....---..-----
................
....................
...
.. .....
...... \{.._ \. 0. 4
................ .................... .,. ..... .... ...... ...-..h
.....
......
,
...
..... ..................
~~~~~~~~~~~...... .....
.........
............
w\......................
.
..
..
.......... X\
.
... ....
. .. .........
............
...
x...
.
............
-
*.......... .......... ........
.. ..
.. .. .. .. _...
.-..
.
....... .
....\.........................
20
E
coCo
2
-
0 19.00
-
07.00
19.00 Time (h)
19.00
07.00
Figure 1 Mean plasma concentration v time curve for five patients on Retard (, 29.5 mg/kg twice daily) and three on Durules (, 28.5 mg/kg twice daily). The shaded area indicates the therapeutic range.
The half-life of Retard was 6.9 h and for Durules was 5.9 h. This is approximately twice the half-life of the conventional oral procainamide preparation. The mean plasma levels plotted against time following the first dose are shown in Figure 2. Again little difference in peak levels reached or rates of decay was evident between the two preparations. (A curve approximating the mean values for both drugs is shown.) Figure 3 combines the results of Durules and Retard to illustrate the difference in pharmacokinetics depending on the time of administration. Table 3 summarizes these results. When the tablets were taken at 07.00 h the half-life was longer and the time-to-peak shorter than when they were taken in the evening.
Discussion
The mean time-to-peak for Retard was 2.0 h which agrees with that obtained by Fremstad, Dahl, Jacobsen, Lunde, Nadland, Marthinsen, Waaler & Landmark (1973) who showed a Tp of 1.8 h. For Durules Tp was 2.6 h which was similar to values obtained by Birkhead, Evans, Mumford, Martinez & Jewitt (1976). There was a wide variation in individual peak values despite the relatively minor dose differences. This was previously reported by Koch-Weser & Klein (1971) and Shaw et al. (1974) using the conventional tablet and more recently by Cunningham, Sloman & Nyberg (1977) with Durules. Ihlen & Ditlefsen (1975) in a clinical trial comparing Durules and Retard reported a consistent
Table 3 Pharmacokinetic results relating to time of administration
Ti (h)
Durules
Tp (h)
Durules
Retard Both Retard Both
Maximum plasma Durules Retard level (pg/ml) Both
07.00h
19.00h
t
doses
doses
(paired)
6.5±1.4 7.9±1.0 7.3 ± 1.3 1.6±0.8 1.5+0.5 1.5±0.6 8.8+ 1.6 7.9+ 2.5 8.2+2.1
5.4+0.7 5.7+1.3 5.6 + 1.0 3.6+1.1 2.5+0.9 3.0+1.1 8.4+ 2.3 7.7+2.1 7.9+2.1
1.45 3.12 3.29 -3.23 -4.88 -4.65 0.31 0.36 0.51
p
NS P < 0.05 P < 0.005 P
A PHARMACOKINETIC COMPARISON OF TWO SUSTAINED-RELEASE ORAL PROCAINAMIDE PREPARATIONS P. HORE, P. BONES, 'T. ROLLINSON & H. IKRAM Department of Cardiology, The Princess Margaret Hospital, Christchurch, New Zealand and ' Department of Biochemistry, Christchurch Public Hospital, Christchurch, New Zealand
1 The pharmacokinetics of two different sustained-release oral procainamide preparations were studied in ten hospital patients with normal blood ureas and no clinical evidence of heart failure. Each patient received either one or other preparation at 12 hourly intervals for four doses. Frequent blood sampling enabled close monitoring of blood levels. 2 Results showed that both preparations were essentially similar in their pharmacokinetics. Both effectively double the half-life of conventional oral procainamide to 6.5 h and are suitable as prophylactic preparations. One patient developed toxic levels, thought to be related to her metabolic status of being a very slow acetylator. To avoid toxicity pre-therapy assessment of a patient's cardiac and renal function and acetylator status is advised.
Introduction
Procainamide hydrochloride is a major antiarrhythmic drug which has been used in the treatment of both atrial and ventricular tachyarrhythmias for over 20 years. It is commonly used to prevent ventricular arrhythmias following myocardial infarction (Koch-Weser, Klein, Foo-Canto, Kastor & Desanctis, 1969; Giardina, Heissenbuttel & Bigger, 1973). Its use as a prophylactic agent has been severely restricted by the short half-life of 3.5 h (Koch-Weser & Klein, 1971) of the conventional oral preparation (Pronestyl, procainamide hydrochloride, Squibb). This has meant that 3 hourly administration of the drug has been necessary to maintain therapeutic plasma levels (Koch-Weser et al., 1969; Shaw, Kumana, Royds, Padgham & Hamer, 1974). To overcome this, sustained-release preparations have recently been developed. This study investigated the relative pharmacokinetics of two such preparations with differing slow release mechanisms. These were Procainamide Durules (Astra: Sweden) and Prokainamid Retard (Collett A/S: Norway). Methods
Procainamide Durules are composed of an insoluble matrix impregnated with 0.5 g procainamide hydrochloride. Prokainamid Retard consists of 0.5 g procainamide hydrochloride in the form of particles coated by a thermoplastic substance, which are
0306-5251/79/090267-05 $1.00
compacted into tablets and further coated by the thermoplastic substance. Ten patients were selected from the cardiology ward and randomly allotted to receive either one or other preparation. The individual dosage ranged from 25-32.5 mg/kg twice daily (Koch-Weser & Klein, 1971; Hansteen, Landmark, Fremstad, Dahl, Jacobsen, Marthinsen, Waaler, Frislid & Lunde, 1976). This amount was given at four 12-hourly intervals. There were six males and four females whose ages ranged from 35 years to 66 years with a mean of 55 years. The clinical details are summarized in Table 1. The patients who were selected fulfilled the following conditions: (i) normal blood urea; (ii) no clinical evidence of cardiac failure; (iii) no myocardial infarction in the previous 72 h. Using these criteria we hoped to avoid those factors known to adversely affect the normal pharmacokinetics of procainamide (Koch-Weser & Klein, 1971; Weily & Genton, 1972). Blood samples were taken at intervals varying from 30 min to 60 min for the first 5 h following each dose, then less frequently in the last 7 h of the 12 hourly cycle. The first dose was given at 19.00 h which was approximately 1.25 h after the evening meal, in all but two cases, when it was given at 07.00 h, approxi5 / 2 $ Macmillan Journals Ltd 1979
268
P. HORE, P. BONES, T. ROLLINSON & H. IKRAM
mately 1 h before breakfast. The samples were assayed by a fluorimetric method (Ambler & Masarei, 1976). The results were analysed for: (i) half-life (TI) (ii) time to peak plasma concentration (Tp) (iii) and (iv) the effect on T, and Tp of taking the drugs before or after meals (v) maximum plasma levels (vi) length of time above the therapeutic minimum (4 ig/ml) (vii) length of time in the potentially toxic range (8-16 jig/ml) (therapeutic and toxic ranges according to Koch-Weser & Klein, 1971).
doses. Her results were atypical as were those of Mrs E.W. and neither are included in the statistical results of Table 2 or the graphs of Figures 1 and 2. They require further explanation and are presented in detail in the Discussion. Table 2 is a summary of the results of the other eight patients. It shows that the pharmacokinetics of the two preparations are very similar. There was no statistically significant difference found between any of the results. Figure 1 shows the mean plasma levels plotted as a function of time for the 48-h period during which the trial was conducted. The first dose is seen to reach a lower maximum level than subsequent doses. For analysis of equilibrium conditions we took the third and fourth curves as being representative. In the equilibrium state Retard and Durules remained above the therapeutic minimum for 67% and 72% of the time respectively. The mean time recorded in the potentially toxic range was 1.2 h for both preparations.
Results
Of the ten patients selected, one did not complete the trial. Mrs D.P. on Durules developed severe toxic symptoms and the drug was stopped after three Table 1 Clinical data
Age (years)
Drug
Dose (mg/kg twice daily)
Mrs I.P. Mr L.C. Mr P.R. Mr L.F. Mrs D.P. Mr F.L.
35 59 49 57 66 59
R R D D D R
27.5 28.5 27.25 32.25 32.5 32.5
Mrs F.McK. Mr G.M. Mrs E.W. Mr R.M.
62 50 64 48
R R D D
30.0 28.5 31.0 26.5
Patient
Diagnosis
Myocardial infarction Chest pain Atrial fibrillation Angina Aortic incomp./controlled left-ventricular failure Hypertension/controlled left-ventricular failure/ aortic incompetence Angina/hypertension Chest pain Investigation of atrial fibrillation Chest pain
(R = Retard, D = Durules).
Table 2 Pharmacokinetic results of eight patients
Mean half-life, TI (h) Mean time-to-peak, Tp (h) Mean maximum levels (pg/mI) Dose I IV Mean time above therapeutic minimum (h) Dose III Dose IV Mean time in potentially toxic range for third and fourth doses (h)
Durules
Retard
t
P
5.9+0.8 2.6+0.5
6.9+1.0 2.0+0.4
1.74
2.18
NS NS
5.8 7.7 9.2 8.0
4.9 7.6 7.6 7.8
NS
7.8 8.2 1.2
8.0 9.2 1.2
NS NS NS NS
Range (0-3.8) Range (0-4.8)
PHARMACOKINETICS OF PROCAINAMIDE
...............................................
269
..................
......................
...............................................
............................................... ...............................................
.....................
................... ..................
............................................... ............................................
..................
.................
.............................................
...................................................
...................................... ..............................................
................ ...............
........................... ..
L .................... e _.................... ~~~~~~~~~~.. t 6 ..........................
__L
wJ ........................ 4*........................ .......................... ...........................
... ^t.......................... .
w.
.......... ...
....
....................... .
..
...
........................
........
...............
_........ ....
.....
...
.............. .
....
~~~~~~~~~~~. .......
---f... --------1....
.................. .. ..........
.
--
.
.
......
\
.....,j.....
..... ... ......
...
...
~~~~~~~~~~~~~.
._.. . .. .. ..
..
................,-
. . ............... .. .\. .
.........
........
. ., ----------.......... ,....... ...... .
....... ................
...........
. s._....
........... ........ .... .... . ... §{^\.......
48.
....
......
*...-....---..-----
................
....................
...
.. .....
...... \{.._ \. 0. 4
................ .................... .,. ..... .... ...... ...-..h
.....
......
,
...
..... ..................
~~~~~~~~~~~...... .....
.........
............
w\......................
.
..
..
.......... X\
.
... ....
. .. .........
............
...
x...
.
............
-
*.......... .......... ........
.. ..
.. .. .. .. _...
.-..
.
....... .
....\.........................
20
E
coCo
2
-
0 19.00
-
07.00
19.00 Time (h)
19.00
07.00
Figure 1 Mean plasma concentration v time curve for five patients on Retard (, 29.5 mg/kg twice daily) and three on Durules (, 28.5 mg/kg twice daily). The shaded area indicates the therapeutic range.
The half-life of Retard was 6.9 h and for Durules was 5.9 h. This is approximately twice the half-life of the conventional oral procainamide preparation. The mean plasma levels plotted against time following the first dose are shown in Figure 2. Again little difference in peak levels reached or rates of decay was evident between the two preparations. (A curve approximating the mean values for both drugs is shown.) Figure 3 combines the results of Durules and Retard to illustrate the difference in pharmacokinetics depending on the time of administration. Table 3 summarizes these results. When the tablets were taken at 07.00 h the half-life was longer and the time-to-peak shorter than when they were taken in the evening.
Discussion
The mean time-to-peak for Retard was 2.0 h which agrees with that obtained by Fremstad, Dahl, Jacobsen, Lunde, Nadland, Marthinsen, Waaler & Landmark (1973) who showed a Tp of 1.8 h. For Durules Tp was 2.6 h which was similar to values obtained by Birkhead, Evans, Mumford, Martinez & Jewitt (1976). There was a wide variation in individual peak values despite the relatively minor dose differences. This was previously reported by Koch-Weser & Klein (1971) and Shaw et al. (1974) using the conventional tablet and more recently by Cunningham, Sloman & Nyberg (1977) with Durules. Ihlen & Ditlefsen (1975) in a clinical trial comparing Durules and Retard reported a consistent
Table 3 Pharmacokinetic results relating to time of administration
Ti (h)
Durules
Tp (h)
Durules
Retard Both Retard Both
Maximum plasma Durules Retard level (pg/ml) Both
07.00h
19.00h
t
doses
doses
(paired)
6.5±1.4 7.9±1.0 7.3 ± 1.3 1.6±0.8 1.5+0.5 1.5±0.6 8.8+ 1.6 7.9+ 2.5 8.2+2.1
5.4+0.7 5.7+1.3 5.6 + 1.0 3.6+1.1 2.5+0.9 3.0+1.1 8.4+ 2.3 7.7+2.1 7.9+2.1
1.45 3.12 3.29 -3.23 -4.88 -4.65 0.31 0.36 0.51
p
NS P < 0.05 P < 0.005 P
