A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Apidra Pharmacology, Pharmacokinetics, Studies, Metabolism - Insulin glulisine
Apidra Pharmacology, Pharmacokinetics, Studies, Metabolism - Insulin glulisine
CLINICAL PHARMACOLOGY
Mechanism of Action
The primary activity of insulins and insulin analogs, including
insulin glulisine, is regulation of glucose metabolism. Insulins lower
blood glucose levels by stimulating peripheral glucose uptake by skeletal muscle
and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis
in the adipocyte, inhibit proteolysis, and enhance protein synthesis.
The glucose lowering activities of APIDRA and of regular human
insulin are equipotent when administered by the intravenous route. After subcutaneous
administration, the effect of APIDRA is more rapid in onset and of shorter duration
compared to regular human insulin.
Pharmacokinetics
Absorption and Bioavailability
Pharmacokinetic profiles in healthy volunteers and patients
with diabetes (type 1 or type 2) demonstrated that absorption of insulin glulisine
was faster than regular human insulin.
In a study in patients with type 1 diabetes (n=20) after subcutaneous
administration of 0.15 IU/kg, the median time to maximum concentration (Tmax)
was 55 minutes (range 34 to 91 minutes) and the peak concentration (Cmax)
was 82 µIU/mL (range 42 to 134 µIU/mL) for insulin glulisine compared to a median
Tmax of 82 minutes (range 52 to 308 minutes) and a Cmax of 46 µIU/mL
(range 32 to 70 µIU/mL) for regular human insulin. The mean residence time of
insulin glulisine was shorter (median: 98 minutes, range 55 to 149 minutes)
than for regular human insulin (median: 161 minutes, range 133 to 193 minutes).
In a euglycaemic clamp study in patients with type 2 diabetes
(n=24) with a body mass index (BMI) between 20 to 36 kg/m2 after
subcutaneous administration of 0.2 IU/kg, the median time to maximum concentration
(Tmax) was 89 minutes (range 74 to 103 minutes) and the median peak
concentration (Cmax) was 81µIU/mL (range 75 to 112 µIU/mL) for insulin
glulisine compared to a median Tmax of 94 minutes (range 55 to140 minutes) and
a median Cmax of 39 µIU/mL ( range 30 to 56 µIU/mL) for regular human insulin.
The mean residence time of insulin glulisine was shorter (median: 154 minutes,
range 122 to 174 minutes) than for regular human insulin (median: 280 minutes,
range 227 to 294 minutes).
In a euglycaemic clamp study in obese, non-diabetic subjects
(n=18) with a body mass index (BMI) between 30 to 40 kg/m2 after
subcutaneous administration of 0.3 IU/kg, the median time to maximum concentration
(Tmax) was 76 minutes (range 51 to 118 minutes) and the median peak
concentration (Cmax) was 199 µIU/mL (range 99 to 387 µIU/mL) for
insulin glulisine compared to a median Tmax of 144 minutes (range
110 to 207 minutes) and a median Cmax of 79 µIU/mL (range 39 to 166
µIU/mL) for regular human insulin. The mean residence time of insulin glulisine
was shorter (median: 141 minutes, range 105 to 210 minutes) than for regular
human insulin (median: 226 minutes, ranging between 188 to 293 minutes).
When APIDRA was injected subcutaneously into different areas
of the body, the time-concentration profiles were similar. The absolute bioavailability
of insulin glulisine after subcutaneous administration is about 70%, regardless
of injection area (abdomen 73%, deltoid 71%, thigh 68%).
Distribution and Elimination
The distribution and elimination of insulin glulisine and regular
human insulin after intravenous administration are similar with volumes of distribution
of 13 L and 21 L and half-lives of 13 and 17 minutes, respectively. After subcutaneous
administration, insulin glulisine is eliminated more rapidly than regular human
insulin with an apparent half-life of 42 minutes compared to 86 minutes.
Pharmacodynamics
Studies in healthy volunteers and patients with diabetes demonstrated
that APIDRA has a more rapid onset of action and a shorter duration of activity
than regular human insulin when given subcutaneously.
In a study in patients with type 1 diabetes (n= 20), the glucose-lowering
profiles of APIDRA and regular human insulin were assessed at various times
in relation to a standard meal at a dose of 0.15 IU/kg.
The maximum blood glucose excursion (GLUmax; baseline
subtracted glucose concentration) for APIDRA injected 2 minutes before meal
was 65 mg/dL compared to 64 mg/dL for regular human insulin injected 30 minutes
before meal, and 84 mg.h/dL for regular human insulin injected 2 minutes before
meal. The maximum blood glucose excursion for APIDRA injected 15 minutes after
the start of a meal was 85 mg/dL compared to 84 mg.h/dL for regular human insulin
injected 2 minutes before meal.
Special Populations
Pediatric Patients
The pharmacokinetic and pharmacodynamic properties of APIDRA
and regular human insulin were assessed in a study conducted in pediatric patients
with type 1 diabetes (children [7 to 11 years, n = 10] and adolescents [12 to
16 years, n = 10]). The relative differences in pharmacokinetics and pharmacodynamics
between APIDRA and regular human insulin in pediatric patients with type 1 diabetes
were similar to those in healthy adult subjects and adults with type 1 diabetes.
Gender
Information on the effect of gender on the pharmacokinetics
of APIDRA is not available.
Race
A study was performed in 24 healthy Caucasians and Japanese
to compare the pharmacokinetic and pharmacodynamic parameters after subcutaneous
injection of insulin glulisine, insulin lispro, and regular human insulin. With
subcutaneous injection of insulin glulisine, Japanese subjects had a greater
initial exposure (33%) for the ratio of AUC(0-1hr) to AUC(0-clamp end) than
that in Caucasians (21%) though the total exposures were similar. Similar findings
were observed with insulin lispro and regular human insulin for the racial difference.
Obesity
The more rapid onset of action and shorter duration of activity
of APIDRA and insulin lispro compared to regular human insulin were maintained
in an obese non-diabetic population (n= 18).
Renal Impairment
Studies with human insulin have shown increased circulating
levels of insulin in patients with renal failure. In a study performed in 24
non-diabetic subjects covering a wide range of renal function (ClCr
>80mL/min; 30-50 mL/min; <30 mL/min), the subjects with moderate and severe
renal impairment showed increased exposure of insulin glulisine by 29% to 40%
and reduced clearance of insulin glulisine by 20 to 25% compared to normal subjects.
Careful glucose monitoring and dose adjustments of insulin, including APIDRA,
may be necessary in patients with renal dysfunction. (See PRECAUTIONS,
Renal Impairment.)
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of
APIDRA has not been studied. Some studies with human insulin have shown increased
circulating levels of insulin in patients with liver failure. Careful glucose
monitoring and dose adjustments of insulin, including APIDRA, may be necessary
in patients with hepatic dysfunction. (See PRECAUTIONS,
Hepatic Impairment.)
Pregnancy
The effect of pregnancy on the pharmacokinetics and pharmacodynamics
of APIDRA has not been studied. (See PRECAUTIONS,
Pregnancy.)
Smoking
The effect of smoking on the pharmacokinetics and pharmacodynamics
of APIDRA has not been studied.
CLINICAL STUDIES
The safety and efficacy of APIDRA was studied in adult patients
with type 1 and type 2 diabetes (n =1833). The primary efficacy parameter was
glycemic control, as measured by glycated hemoglobin (GHb), and expressed as
hemoglobin A1c equivalents (HbA1c).
Type 1 Diabetes:
A 26-week, randomized, open-label, active-control study was
conducted in patients with type 1 diabetes to assess the safety and efficacy
of APIDRA (n= 339) compared to insulin lispro (n= 333) when administered subcutaneously
within 15 minutes before a meal. Lantus (insulin glargine)† was administered
once daily in the evening as the basal insulin. There was a 4-week run-in period
combining insulin lispro and Lantus followed by randomization. Most patients
were Caucasian (97%). Fifty eight percent of the patients were male. The mean
age was 38.5 years (range 18 to 74 years). Glycemic control (see Table 1) and
the rates of hypoglycemia requiring intervention from a third party (see Adverse
Reactions), were comparable for the two treatment regimens. The number
of daily short-acting insulin injections and the total daily doses of APIDRA
and insulin lispro were similar. (See Table 1.)
|
Table 1: Type 1 Diabetes Mellitus–Adult
|
|
Treatment duration
|
26 weeks Lantus®
|
|
Treatment in combination with:
|
APIDRA
|
Insulin Lispro
|
|
HbA1c (%)
|
|
|
|
Number of patients
|
331
|
322
|
|
Baseline mean
|
7.60
|
7.58
|
|
Adj. mean change from baseline
|
-0.14
|
-0.14
|
|
APIDRA – Insulin Lispro
|
0.00
|
|
95% CI for treatment difference
|
(-0.09; 0.10)
|
|
Basal insulin dose (IU/day)
|
|
|
|
Endstudy mean
|
24.16
|
26.43
|
|
Adj. mean change from baseline
|
0.12
|
1.82
|
|
Short-acting insulin dose (IU/day)
|
|
|
|
Endstudy mean
|
29.03
|
30.12
|
|
Adj. mean change from baseline
|
-1.07
|
-0.81
|
|
Mean number of short-acting insulin injections per day
|
3.36
|
3.42
|
Type 2 Diabetes:
A 26-week, randomized, open-label, active-control study was
conducted in insulin-treated patients with type 2 diabetes to assess the safety
and efficacy of APIDRA (n= 435) given within 15 minutes before a meal compared
to regular human insulin (n=441) administered 30 to 45 minutes prior to a meal.
NPH human insulin was given twice a day as the basal insulin. All patients participated
in a 4-week run-in period combining regular human insulin and NPH human insulin.
Eighty-five percent of patients were Caucasian and 11% were Black. The mean
age was 58.3 years (range 26 to 84 years). The average body mass index (BMI)
was 34.55 kg/m2. At randomization, 58% of the patients were on an
oral antidiabetic agent and were instructed to continue use of their oral antidiabetic
agent at the same dose. The majority of patients (79%) mixed their short-acting
insulin with NPH human insulin immediately prior to injection. The reductions
from baseline in HbA1c were similar between treatment groups (see Table 2).
The rates of hypoglycemia, requiring intervention from a third party, were comparable
for the two treatment regimens (see Adverse Reactions).
No differences between APIDRA and regular human insulin groups were seen in
the number of daily short-acting insulin injections or basal or short-acting
insulin doses. (See Table 2.)
|
Table 2: Type 2 Diabetes Mellitus–Adult
|
|
Treatment duration
|
26 weeks NPH human insulin
|
|
Treatment in combination with:
|
APIDRA
|
Regular Human
|
|
|
|
Insulin
|
|
HbA1C (%)
|
|
|
|
Number of patients
|
404
|
403
|
|
Baseline mean
|
7.57
|
7.50
|
|
Adj. mean change from baseline
|
-0.46
|
-0.30
|
|
APIDRA – Regular Human Insulin
|
-0.16
|
|
95% CI for treatment difference
|
(-0.26; -0.05)
|
|
Basal insulin dose (IU/day)
|
|
|
|
Endstudy mean
|
65.34
|
63.05
|
|
Adj. mean change from baseline
|
5.73
|
6.03
|
|
Short-acting insulin dose (IU/day)
|
|
|
|
Endstudy mean
|
35.99
|
36.16
|
|
Adj. mean change from baseline
|
3.69
|
5.00
|
|
Mean number of short-acting insulin injections per day
|
2.27
|
2.24
|
Pre- and Post-Meal Administration (Type 1 Diabetes):
A 12-week, randomized, open-label, active-control study was
conducted in patients with type 1 diabetes to assess the safety and efficacy
of APIDRA administered at different times with respect to a meal. APIDRA was
administered subcutaneously either within 15 minutes before a meal (n=286) or
immediately after a meal (n=296) and regular human insulin (n= 278) was administered
subcutaneously 30 to 45 minutes prior to a meal. Lantus was administered once
daily at bedtime as the basal insulin. There was a 4-week run-in period combining
regular human insulin and Lantus followed by randomization. Most patients were
Caucasian (94%). The mean age was 40.3 years (range 18 to 73 years). Glycemic
control (see Table 3) and the rates of hypoglycemia requiring intervention from
a third party (see Adverse Reactions) were
comparable for the treatment regimens. No changes from baseline between the
treatments were seen in the total daily number of short-acting insulin injections.
(See Table 3.)
|
Table 3: Type 1 Diabetes Mellitus–Adult
|
|
Treatment duration
|
12 weeks
|
12 weeks
|
12 weeks
|
|
Treatment in combination with:
|
Lantus®
|
Lantus®
|
Lantus®
|
| |
APIDRA
|
APIDRA
|
Regular Human
|
| |
pre meal
|
post meal
|
Insulin
|
|
HbA1c
|
|
|
|
| |
Number of patients
|
268
|
276
|
257
|
| |
Baseline mean
|
7.73
|
7.70
|
7.64
|
| |
Adj. mean change from baseline*
|
-0.26
|
-0.11
|
-0.13
|
|
Basal insulin dose (IU/day)
|
|
|
|
| |
Endstudy mean
|
29.49
|
28.77
|
28.46
|
| |
Adj. mean change from baseline
|
0.99
|
0.24
|
0.65
|
|
Short-acting insulin dose (IU/day)
|
|
|
|
| |
Endstudy mean
|
28.44
|
28.06
|
29.23
|
| |
Adj. mean change from baseline
|
-0.88
|
-0.47
|
1.75
|
|
Mean number of short-acting insulin injections per day
|
3.15
|
3.13
|
3.03
|
|
* Adj. mean change from baseline treatment difference
(98.33% CI for treatment difference): APIDRA pre meal vs. Regular Human
Insulin - 0.13 (-0.26; 0.01); APIDRA post meal vs. Regular Human Insulin
0.02 (-0.11; 0.16); APIDRA post meal vs. pre meal 0.15 (0.02; 0.29).
|
Continuous Subcutaneous Insulin Infusion (CSII) (Type 1
Diabetes):
To evaluate the use of APIDRA for administration using an external
pump, a 12-week randomized, active control study (APIDRA versus insulin aspart)
was conducted in patients with type 1 diabetes (APIDRA n= 29, insulin aspart
n=30). All patients were Caucasian. The mean age was 45.8 (range 21-73 years).
Glycemic control (mean HbA1c value at endpoint 6.98% with APIDRA and 7.18% with
insulin aspart) and the rates of hypoglycemia requiring intervention from a
third party were comparable for the two treatment regimens.
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