g;, exert their specific action through binding to insulinreceptors. Receptor-bound insulin lowers blood glucose byfacilitating cellular uptake of glucose into skeletal muscle andadipose tissue and by inhibiting the output of glucose from the liver.
Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, andenhances protein synthesis.
12.2 Pharmacodynamics
The time course of insulin action (i.e., glucose lowering) may varyconsiderably in different individuals or within the same individual.
The average pharmacodynamic profile [i.e., glucose loweringeffect measured as glucose infusion rate (GIR) in a euglycemicclamp study] for subcutaneous administration of 0.1, 0.2, and 0.4unit/kg of FIASP® in 46 patients with Type 1 diabetes is shownin Figure 2 and key characteristics of the timing of the effect aredescribed in Table 5 below.
Table 5. Timing of insulin effect (i.e., mean
pharmacodynamic effect) after subcutaneous
administration of 0.1, 0.2 and 0.4 unit/kg of FIASP® in
patients (N=46) with Type 1 Diabetes and corresponding
to the data shown in Figure 2
Parameter for Insulin Effect FIASP®
0.1 unit/kg
FIASP®
0.2 unit/kg
FIASP®
0.4 unit/kg
Time to first measurable effect ~20 minutes ~17 minutes ~16 minutes
Time to peak effect ~91 minutes ~122
minutes
~133
minutes
Time for effect to return to baseline ~5 hours ~6 hours ~7 hours
10
8
6
4
2
0
0
Insulin Effect (GIR; mg/(kg*min))
60 120
0.1 0.2 0.4
180 240
Time (min)
FIASP® Dose Level (unit/kg).
300 360 420
Figure 2. Mean insulin effect (i.e., mean
pharmacodynamic effect) over time after subcutaneousadministration of 0.1, 0.2 and 0.4 unit/kg of FIASP® inpatients (N=46) with Type 1 diabetesOn average, the pharmacodynamic effects of FIASP®, measuredas area under the glucose infusion rate-time curve (AUCGIR), was697 mg/kg, 1406 mg/kg, and 2427 mg/kg following administrationof 0.1, 0.2, and 0.4 unit/kg of FIASP®.
The day-to-day variability in glucose-lowering-effect of FIASP®within patients was ~18% for total glucose lowering (AUCGIR, 0-12h)and ~19% for maximum glucose lowering effect (GIRmax).
12.3 Pharmacokinetics
Absorption
Pharmacokinetic results from a euglycemic clamp study in adultpatients with type 1 diabetes (N=51) showed that insulin aspartappeared in the circulation ~2.5 minutes after administration ofFIASP® (Figure 3). Time to maximum insulin concentrations wasachieved ~63 minutes after administration of FIASP®.
600
550
500
450
400
350
300
250
200
150
100
50
0
0 60 120 180 240 300 360
Insulin aspart concentration (pmol/L)
Time (min)
FIASP®
Figure 3. Mean Insulin Aspart Serum ConcentrationProfile in Adult Subjects with Type 1 Diabetes (N=51)following a single 0.2 unit/kg dose (subcutaneous) ofFIASP®
Total insulin exposure and maximum insulin concentration increaseproportionally with increasing subcutaneous dose of FIASP® withinthe therapeutic dose range.
Distribution
Insulin aspart has a low binding affinity to plasma proteins (<10%),similar to that seen with regular human insulin.
Elimination
The apparent terminal half-life after subcutaneous administration ofFIASP® is about 1.1 hours.
Specific Populations
Age (18 to ≥65 years), gender, BMI, and race did not meaningfullyaffect the pharmacokinetics and pharmacodynamics of FIASP®.
Pregnant Women
T |
