Apidra (insulin glulisine) - Sanofi Canada

Species/
Strain
Himalayan
rabbits
Himalayan
rabbits
Himalayan
rabbits
Route Dosage/Duration
Subcutaneous Insulin glulisine once
daily as a solution in
placebo solution at
the dose levels of 0,
2, 10 or 50 U/kg
body weight from
day 6 - 18 of
pregnancy
Subcutaneous Dose levels of 0,
0.25, 0.50 or 1.50
U/kg body weight of
insulin glulisine or
HR1799 at the dose
levels of 0.25 or 1.50
U/kg body weight,
once daily as a
solution in placebo
from day 6 - 18 of
pregnancy
Subcutaneous Insulin glulisine once
daily as a solution in
placebo solution at
the dose levels of
0.25, 0.5 or 1.5 U/kg
body weight from
day 6 - 12 of
pregnancy
HR1799 = Reference compound (human insulin)
No. of Animals/
Group
Groups of 6
mated female
Groups of 20-26
mated female
Groups of 10
mated females
Findings
• Treatment–related mortality and clinical
signs due to hypoglycemia were seen at all
dose levels tested.
• Food consumption was slightly higher at
the dose levels of 2 and 10 U/kg.
• The animals found dead exhibited only
empty implantation sites or conceptuses in
the uterus. Foetal weight and crown/rump
lengths were not altered in the dose
groups. The number of intrauterine deaths
was higher in the 2 and 10 U/kg group.
• Based on the results of this study, the dose
of 1.5 U insulin glulisine / kg body weight
per day is considered to be a suitable high
dose for the main study.
• Administration of both insulin glulisine and
HR1799 caused clinical signs and mortality
at the daily dose of 1.5 U/kg body weight.
• The incidence of dams with total litter loss
and the incidence of resorptions were
increased. Morphological examination of
the fetuses revealed an increased
incidence of fetuses showing anomalies in
the region of vertebral column and ribs.
• Clinical signs were also observed in one
animal from the group dosed with 0.5 U
insulin glulisine/kg body weight. The
incidence of resorptions was slightly
increased in this group. No compoundrelated
effects were observed by
morphological examination of the fetuses.
• With regard to the present study the No
Observable Adverse Effect Level is at the
daily dose of 0.25 U insulin glulisine/kg
body weight and at the daily dose of 0.25 U
HR1799/kg body weight for maternal and
developmental effects.
• The animal of the 1.5 U/kg group found
dead exhibited only 5 corpora lutea.
• The insulin glulisine pharmacokinetic
parameters following the 7th administration
are found below:
At 0.25 U/kg tmax : 0.25 h Cmax: 7.8ng/ml
At 0.5 U/kg tmax : 0.25 h Cmax: 15.3ng/ml
At 1.5 U/kg tmax : 0.50 h Cmax: 80.2ng/ml
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