| oseltamivir (free base) dose (mg/kg) |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
rate of death (total) |
| dose-finding |
Pre-1 Tx *a |
Pre-1 TK |
Pre-2 Tx |
Pre-2 TK *b |
Post M Tx |
Post M TK *c |
| Rds |
d |
rate |
Rds |
d |
rate |
Rds |
d |
rate |
Rds |
d |
rate |
Rds |
d |
rate |
Rds |
d |
rate |
Rds |
d |
rate |
Rds |
d |
rate |
| 0 |
24 |
0 |
0 |
48 |
0 |
0 |
48 |
0 |
0 |
14 |
0 |
0 |
|
|
|
20 |
0 |
0 |
96 |
0 |
0 |
250 |
0 |
0 |
| 38 |
24 |
0 |
0 |
48 |
0 |
0 |
30.6 |
0 |
0 |
|
|
|
|
|
|
|
|
|
|
|
|
102.6 |
0 |
0 |
| 114 |
24 |
0 |
0 |
48 |
0 |
0 |
30.6 |
0 |
0 |
|
|
|
|
|
|
|
|
|
|
|
|
102.6 |
0 |
0 |
| 300 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
20 |
0 |
0 |
58.3 |
1 |
1.7 |
78.3 |
1 |
1 |
| 380 |
24 |
0 |
0 |
48 |
0 |
0 |
30.6 |
0 |
0 |
14 |
0 |
0 |
|
|
|
|
|
|
|
|
|
116.6 |
0 |
0 |
| 500 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
20 |
0 |
0 |
58.3 |
3 |
5 |
78.3 |
3 |
4 |
| 533 |
|
|
|
|
|
|
|
|
|
14 |
2 |
14 |
|
|
|
|
|
|
|
|
|
14 |
2 |
14 |
| 600 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
20 |
3 |
15 |
58.3 |
7 |
12 |
78.3 |
10 |
13 |
| 700 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
20 |
7 |
35 |
58.3 |
16 |
27 |
78.3 |
23 |
29 |
| 761 *d |
24 |
18 |
75 |
|
|
|
|
|
|
14 |
3 |
21 |
34.8 |
7 |
20 |
|
|
|
|
|
|
72.8 |
28 |
38 |
| 850 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
20 |
11 |
55 |
58.3 |
38 |
65 |
78.3 |
49 |
63 |
| 1000 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
20 |
19 |
95 |
58.3 |
51 |
87 |
78.3 |
70 |
89 |
| """Rate"" or ""rate of death"" is expressed as number of deaths (d) per 100 rats-days (Rds). d: number of rats that died.
For the TK tests, denominators were expressed as rat-days (Rds), calculated using the number of rats sacrificed for determination of plasma and brain concentration at each time point. Data from ref. [28,29,38,39]. For example, in study 7 (Post M TK), 6 rats each were withdrawn at 0.25, 0.5,1,1.5, 2,4, and 8 hours before the end of observation and the last measurement. Chi square for linear trend = 432.1, P<0.0001.
Dose of oseltamivir and proportion of death in 7-day old rats using the number of rats at the start of the studies as denominators is shown in Figure 1.
*a: Pre-1：before approval of oseltamivir for children
*b: Pre-2: before approval of oseltamivir capsule for prophylaxis
*c: Post-M: post-marketing toxicity study;Tx: toxicity study; TK: toxicokinetic study
*d: High mortality may be due to the rats having lower body weight. Although their weights were not shown, the rats used in the Pre-1 Tx and TK studies weighed less (11.5 to 18.9 g) than those in studies 4 and 5 (14.0 to 26.0), which means they were less grown. Body weight of the rats in post-marketing Tx and post-marketing TK studies were not shown.
Data from ref [34,35,46,48,49]".
Rate is expressed as number of deaths per 100 rats-days. d: number of rats that died. |
|
