|
NDA
20-358 |
3 |
A)
Dosage
Doses and numbers of animals are shown below. Note that 3 dose levels of “degraded” drug were used (see Summary section for amounts of degradants) along with one dose level of undegraded drug (hereafter referred to as HD*, equal to the HD of degraded drug). Note 4/sex/dose were used for a 14 day recovery period. Dosing was by gavage.
Strain:
Charles River RD
|
GROUP NO. |
SUBSTANCE |
DOSE (MG/KG/DAY) |
TOTAL NO.a OF
ANIMALS (MALE/FEMALE) |
TOX STUDY UAIN (93-PREFIX) |
|
|
|
|
|
|
MALE |
FEMALE |
|
1 |
Sterile
Water |
0 |
14/14 |
6025-6038 |
6150-6163 |
|
2 |
323U66
HClb |
75 |
14/14 |
6039-6052 |
6164-6177 |
|
3 |
323U66
HClb |
150 |
14/14 |
6053-6066 |
6178-6191 |
|
4 |
323U66
HClb |
300 |
14/14 |
6067-6080 |
6192-6205 |
|
5 |
323U66
HClb |
300 |
14/14 |
6081,
6143, 6083, 6084, 6144d, 6086-6088, 6145d-6090, 6146d,
6092-9094 |
6206-6219 |
|
6c |
323U66
HClb |
75 |
12/12 |
6094-6106 |
6220-6231 |
|
7c |
323U66
HClb |
150 |
12/12 |
6107-6118 |
6232-6243 |
|
8c |
323U66
HClb |
300 |
12/12 |
6119-6130 |
6244-6255 |
|
9c |
323U66
HClb |
300 |
12/12 |
6131-6142 |
6256-6267 |
a
Four
males and four females in groups 1-5 were assigned to a 14-day postdose
recovery period.
b Degraded 323U66 HCl
c Groups 6-9 for drug plasma
level determinations. Only body weights
and observations for clinical signs of toxicity were evaluated.
d Replacement animals on dose
day 4.
B)
Results
1)
Observed
signs
D-R postdosing salivation at all doses; it was
stated that there was no difference between HD and HD* “with respect to
incidence or frequency of occurrence”.
2)
Mortality
Results summarized on attached page. There was an excess of deaths at HD*; however, most of these were “confirmed to be caused by dosing accidents”.
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