Three Patients Needing High Doses of Valproic Acid to Get Therapeutic Concentrations
Table 4
VPA C/D ratio in Case 3.
Day1
VPA
Phenytoin
Formulation
Dose1 (mg/day)
Concentration (μg/mL)
C/D ratio
C/D ratio × 1000
Dose (mg/day)
Concentration (μg/mL)
All 137 VPA concentrations (C/D ratio × 1000: mean ± SD = 8 ± 3.5, range = 3–20)
70 therapeutic2 VPA concentrations (C/D ratio × 1000: mean ± SD = 9 ± 3.4, range = 5–18)
13
ECDVNa
3375
46
0.014
14
500
15
333
ECDVNa
3375
59
0.017
17
500
18
623
ECDVNa
3375
43
0.013
13
500
16
863
Concentrate
3350
22
0.007
7
500
1173
ECDVNa
3450
43
0.012
12
500
11
1473
ECDVNa
3375
38
0.011
11
500
10
1623
Concentrate
3450
9
0.003
3
500
1743
Concentrate
3450
28
0.008
8
500
18
1773
Concentrate
3450
31
0.009
9
500
18
1893
ECDVNa
3375
36
0.011
11
500
2023
ECDVNa
3750
40
0.011
11
500
10
2083
ECDVNa
4125
40
0.010
10
500
14
2123
ECDVNa
4500
68
0.015
15
500
15
2443
ECDVNa
4500
61
0.014
14
500
15
2743
ECDVNa
4500
67
0.015
15
500
15
3073
ECDVNa
4500
46
0.010
10
500
23
3103
ECDVNa
4500
50
0.011
11
0
23
3133
ECDVNa
4500
39
0.009
9
500
10
3163
ECDVNa
4500
81
0.018
18
500
11
3203
ECDVNa
4500
31
0.007
7
500
15
3243
ECDVNa
4500
46
0.010
10
500
16
3353
ECDVNa
5000
64
0.013
13
500
19
3503
ECDVNa
5000
75
0.015
15
500
24
3983
ECDVNa
5000
52
0.010
10
460
16
4003
ECDVNa
5000
85
0.017
17
460
11
4303
ECDVNa
5000
59
0.012
12
460
16
4393
ECDVNa
5000
65
0.013
13
460
18
4703
ECDVNa
5000
54
0.011
11
460
16
5023
ECDVNa
5000
53
0.011
11
460
20
5304
ECDVNa
5000
77
0.015
15
460
17
5594
ECDVNa
5000
50
0.010
10
460
13
5905
ECDVNa
5000
48
0.010
10
460
12
6216
ECDVNa
5000
37
0.007
7
460
10
6356
ECDVNa
5000
39
0.008
8
460
11
6466
ECDVNa
5250
35
0.007
7
460
13
6817
ECDVNa
5250
37
0.007
7
460
8
7137
ECDVNa
5250
46
0.009
9
460
7
7347
ECDVNa
5250
40
0.008
8
460
10
7627
ECDVNa
6000
53
0.009
9
460
9
7707
ECDVNa
6000
43
0.007
7
460
8
7987
ECDVNa
6000
23
0.004
4
460
9
8067
ECDVNa
6000
32
0.005
5
460
10
8177
ECDVNa
7500
36
0.005
5
200
9
8317
ECDVNa
7500
43
0.006
6
460
5
8387
ECDVNa
7500
47
0.006
6
460
15
8467
ECDVNa
7500
24
0.003
3
460
10
8527
ECDVNa
7500
35
0.005
5
460
8
8607
ECDVNa
7500
51
0.007
7
460
8667
ECDVNa
7500
42
0.006
6
460
3
8887
ECDVNa
7500
71
0.009
9
460
20
8907
ECDVNa
7500
81
0.011
11
460
20
9167
ECDVNa
7500
45
0.006
6
460
7
9197
ECDVNa
7500
46
0.006
6
460
7
9297
ECDVNa
8250
43
0.005
5
460
9437
ECDVNa
9000
43
0.005
5
460
9507
ECDVNa
9000
50
0.006
6
460
9577
ECDVNa
9000
75
0.008
8
460
9647
ECDVNa
9000
37
0.004
4
460
9717
ECDVNa
9000
28
0.003
3
460
9727
ECDVNa
9000
44
0.005
5
460
8
9797
ECDVNa
9000
64
0.007
7
460
6
9857
ECDVNa
9000
38
0.004
4
460
9
9897
ECDVNa
9000
50
0.006
6
460
8
9927
ECDVNa
9000
59
0.007
7
460
9
9997
ECDVNa
9000
54
0.006
6
460
6
10147
ECDVNa
9000
35
0.004
4
460
6
10207
ECDVNa
9000
42
0.005
5
460
5
10297
ECDVNa
10500
43
0.004
4
460
7
10357
ECDVNa
10500
102
0.010
10
460
6
10397
ECDVNa
10500
54
0.005
5
460
1
10427
ECDVNa
10500
77
0.007
7
460
6
10567
ECDVNa
10500
120
0.011
11
460
6
10627
ECDVNa
10500
39
0.004
4
460
8
10647
ECDVNa
10500
47
0.004
4
460
7
10707
ECDVNa
10500
56
0.005
5
460
6
10807
ECDVNa
10500
51
0.005
5
460
10
10917
ECDVNa
10500
54
0.005
5
460
11
10987
ECDVNa
10500
63
0.006
6
460
12
11057
ECDVNa
10500
49
0.005
5
460
12
11127
ECDVNa
10500
47
0.004
4
460
8
11197
ECDVNa
10500
51
0.005
5
460
6
11337
ECDVNa
10500
91
0.009
9
460
7
11487
ECDVNa
10500
50
0.005
5
460
13
11637
ECDVNa
10500
40
0.004
4
460
9
11687
ECDVNa
10500
62
0.006
6
460
10
11757
ECDVNa
10500
63
0.006
6
460
13
11827
ECDVNa
10500
110
0.010
10
460
11
11847
ECDVNa
10500
61
0.006
6
460
10
11897
ECDVNa
10500
56
0.005
5
460
10
11967
ECDVNa
14000
133
0.010
10
460
9
12107
ECDVNa
10500
67
0.006
6
460
13
12177
ECDVNa
10500
65
0.006
6
460
14
12247
ECDVNa
10500
87
0.008
8
460
11
12317
ECDVNa
10500
70
0.007
7
460
13
12457
ECDVNa
10500
65
0.006
6
460
15
12527
ECDVNa
10500
97
0.009
9
460
9
12597
ECDVNa
10500
77
0.007
7
460
13
12667
ECDVNa
10500
56
0.005
5
460
12
12737
ECDVNa
10500
97
0.009
9
460
14
12807
ECDVNa
10500
60
0.006
6
460
16
12878
ECDVNa
10500
39
0.004
4
460
19
12948
ECDVNa
10500
103
0.010
10
460
15
13018
ECDVNa
10500
48
0.005
5
460
19
13078
ECDVNa
10500
72
0.007
7
460
13
13168
ECDVNa
10500
54
0.005
5
460
13
13228
ECDVNa
10500
71
0.007
7
460
13
13298
ECDVNa
10500
75
0.007
7
460
13
13368
ECDVNa
10500
98
0.009
9
460
12
13448
ECDVNa
10500
93
0.009
9
460
11
13508
ECDVNa
10500
65
0.006
6
460
15
13578
ECDVNa
10500
58
0.006
6
460
23
13648
ECDVNa
10500
73
0.007
7
460
18
13718
ECDVNa
10500
106
0.010
10
460
24
13738
ECDVNa
10500
106
0.010
10
460
20
13788
ECDVNa
10500
89
0.008
8
460
15
13868
ECDVNa
10500
97
0.009
9
460
17
13928
ECDVNa
10500
72
0.007
7
460
21
13938
ECDVNa
10500
87
0.008
8
460
23
13948
ECDVNa
10500
122
0.012
12
230
22
13958
ECDVNa
3500
37
0.011
11
0
20
13998
ECDVNa
10500
130
0.012
12
400
8
14068
ECDVNa
10500
94
0.009
9
400
10
14138
ECDVNa
10500
126
0.012
12
400
12
14208
ECDVNa
10500
108
0.010
10
400
12
14278
ECDVNa
6000
59
0.010
10
400
21
14358
ECDVNa
9000
110
0.012
12
400
5
14408
ECDVNa
9000
86
0.010
10
400
8
14448
ECDVNa
9000
82
0.009
9
400
10
14488
ECDVNa
9000
147
0.016
16
400
10
14547
ECDVNa
7000
93
0.013
13
400
14
14579
ECDVNa
7000
138
0.020
20
400
11
146110
ECDVNa
7000
72
0.010
10
400
13
147011
ECDVNa
7000
101
0.014
14
400
13
1478
ECDVNa
7000
113
0.016
16
400
7
1483
ECDVNa
7000
97
0.014
14
400
6
C/D: concentration-to-dose; ECDVNa: enterocoated divalproex sodium; VPA: valproic acid. 1After day 1420, VPA dose was guided more by physical comfort than VPA concentrations; therefore, these latter days were eliminated to calculate the Pearson correlation between day of admission and VPA dose, which was (); VPA dose remained very high in a partial correlation while controlling for VPA concentration: (). This is compatible with a progressive autoinduction indicating, at least with dose range, that it was necessary to increase the dose as the duration lengthened. When all values (including those after day 1420) were used to calculate correlations, the values were, not surprisingly, slightly reduced both for the total correlation of () and the partial correlation of (). 250–100 μg/mL concentrations are considered therapeutic concentrations. As this patient has too many nontherapeutic concentrations, it may be better to compare with other patients using only the VPA therapeutic concentrations. 3Other scheduled oral medications included benztropine 4 mg/day, mesoridazine 200 mg/day, lorazepam 6 mg/day, and risperidone 12 mg/day. 4Other scheduled oral medications included benztropine 4 mg/day, lorazepam 6 mg/day, and risperidone 12 mg/day. 5Other scheduled oral medications included benztropine 4 mg/day, lorazepam 6 mg/day, and risperidone 4 mg/day. 6Other scheduled oral medications included benztropine 4 mg/day and lorazepam 6 mg/day. 7Other scheduled oral medications included lorazepam 6 mg/day. 8Other scheduled oral medications included lorazepam 6 mg/day and trazodone 150 mg/day. 9Other scheduled oral medications included lorazepam 4 mg/day. 10Other scheduled oral medications included lorazepam 3 mg/day. 11Other scheduled oral medications included lorazepam 1 mg/day.