Dosage Interval: RESULTSPatient Response

Five of the 31 patients who were admitted and received 8-h treatment were dropped from the study because of protocol violations. Of the 26 remaining patients, 17 responded to the 8-h regimen with the desired degree of PVC suppression. Predictably, the rate of response to the initial 8-h therapy was higher in the group that had been effectively treated with mexiletine before the study than in the group that was receiving the drug for the first time.

Administration of mexiletine on the 12-h schedule led to target reduction of ventricular arrhythmia in 15 (88 percent) of the 17 patients treated on this schedule. The baseline hourly rate of PVCs in the 17 patients averaged 263. During treatment with mexiletine every 8 h this rate was reduced to a mean of 29 (a mean reduction of 83 percent); treatment every 12 h reduced the baseline rate to 59 PVCs per hour (a mean reduction of 77 percent). Median reductions amounted to 86 and 90 percent on the 8- and 12-h schedules, respectively.

The mean hourly PVC rates after mexiletine given either every 8 or 12 h were significantly (p<0.01) lower than the baseline PVC rates. There was no significant difference (p = 0.09) between the first and second baseline PVC rates. Intervals between the two baseline Holter recordings averaged 7.6 h. The periods elapsing between the baseline Holter recordings and the last Holter recording obtained during treatment averaged eight days (range, 5 to 19 days) for the 8-h regimen and 19.4 days (range, 9 to 42 days) for the 12-h.

FIGURE 1. Median numbers of PVCs in each hour of a 24-h period before treatment and during 8- and 12-h mexiletine administration in the 17 patients who responded to the 8-h dosing regimen.

There was no significant difference between the responses to the two dosing regimens (p = 0.53 and p = 0.60 for rates and percent reductions from base­line, respectively).

The time course of the median PVC frequency at baseline and on the two different dosing schedules during a 24-h period is shown in Figure 1. At both dosage intervals, the diurnal variations observed be­fore treatment were virtually absent after mexiletine administration, and the curves of the median numbers of PVCs recorded each hour nearly coincide on the two dosage schedules.

Couplets were reduced from a mean hourly baseline rate of 1.5 to a post-mexiletine rate of 0.1 on both the 8- and 12-h regimens. A mean baseline rate of 0.2 episodes of ventricular tachycardia per hour was reduced to a mean of 0.02 on the 8-h and of 0.01 on the 12-h schedule.

Table 1—Daily Dose Levels, Hourly PVC Rates and Percentage Reductions from Baseline in Each of 17 Patients. Treated Both Every 8 and 12 h

q8h

ql2h

%PVC

%PVC

Daily

Reduction

Daily

Reduction

Patient

Baseline

Dose

from

Dose

from

No.

PVC/h

(mg)

PVC/h

Baseline

(mg)

PVC/h

Baseline

1

91.7

300

32.8

64

400

14.4

84

2

471.0

600

64.8

86

900

6.5

99

3

485.3

600

40.5

92

600

50.3

90

4

755.5

900

0.8

100

900

78.2

90

5

309.5

600

23.2

92

600

18.4

94

6

113.7

600

0.1

100

600

0.6

99

7

61.8

900

17.2

72

600

4.7

92

8

123.5

600

11.7

90

700

15.3

88

9

63.9

300

18.5

71

600

6.2

90

10

206.2

900

32.7

84

600

42.2

79

11

52.6

900

7.5

86

600

10.0

81

12

286.2

600

100.0

65

900

52.9

82

13

66.8

300

12.9

81

600

4.6

93

14

41.1

600

1.9

95

700

1.5

96

15

921.0

300

1.3

100

600

1.5

100

16

379.5

600

102.2

73

400

668.0

-76*

17

45.9

600

18.0

61

700

31.4

32

Dosage

For the 17 patients who were treated on both schedules, the mean daily dose was 600 mg every 8 h and 647 mg every 12 h. Individual changes in the daily dose from 8 to 12 h are shown in Figure 2. Although the protocol specified that 12-h dosage should begin with 600 mg daily, concerns about tolerability based on experience with the 8-h regimen caused two patients to receive only 200 mg every 12 h. Generally, the patients required the same or slightly higher daily doses on the 12-h than on the 8-h schedule. Table 1 gives each patients daily dose together with hourly PVC rates and percent reductions from baseline on the two dosage schedules.

FIGURE 2. Changes in daily dose in milligrams from 8- to 12-h dosage (n = 17) (No. of lines = No. of patients).