Table 1.
Mortality of 7‐day‐old rats from toxicity tests (Tx) and toxicokinetic (TK) tests
| Oseltamivir (free base) dose (mg/kg) | 1 | 2 | 3 | 4 | 5 | 6 | 7 | Rate of death (total) | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose‐finding | Pre‐1 Txa | Pre‐1 TK | Pre‐2 Tx | Pre‐2 TK b | Post‐M Txc | Post‐M TKc | ||||||||||||||||||
| 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 | |||||||||||||||
| 761d | 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 | |||||||||||||||
Data from Refs. 34, 35, 50, 51, 52. “Rate” or “rate of death” is expressed as number of deaths (d) per 100 rat‐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 concentrations at each time point. For example, in study 7 (Post‐M TK), six rats each were withdrawn at 0.25, 0.5, 1, 1.5, 2, 4 and 8 hours before the end of observation and the last measurement.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 value for linear trend=432.1, P<.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 are shown in Fig. 1.
Pre‐1:before approval of oseltamivir for children,
Pre‐2: before approval of oseltamivir capsule for prophylaxis.
Post‐M: post‐marketing toxicity study. Tx: toxicity study. TK: toxicokinetic study.
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 (11.5–18.9 g) than those in studies 4 and 5 (14.0–26.0), which means they were less grown. Body weight of the rats in post‐marketing Tx and post‐marketing TK studies were not shown.