Apidra - Pharmacology insulin glulisine

Pharmacology refers to the chemical makeup and behavior of APIDRA (insulin glulisine injection, solution).

Description

APIDRA® (insulin glulisine injection) is a rapid-acting human insulin analog used to lower blood glucose. Insulin glulisine is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12). Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. Chemically, insulin glulisine is 3B-lysine-29B-glutamic acid-human insulin, has the empirical formula C25 8H38 4N6 4O7 8S6 and a molecular weight of 5823 and has the following structural formula:

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APIDRA (insulin glulisine injection) is a sterile, aqueous, clear, and colorless solution for subcutaneous or intravenous use. Each milliliter of APIDRA contains 100 units (3.49 mg) insulin glulisine, 3.15 mg metacresol, 6 mg tromethamine, 5 mg sodium chloride, 0.01 mg polysorbate 20, and water for injection. APIDRA has a pH of approximately 7.3. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and/or sodium hydroxide.

Clinical Pharmacology

mechanism of action

Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

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 units/kg (see Figure 1).

The maximum blood glucose excursion (ΔGLUmax; baseline subtracted glucose concentration) for APIDRA injected 2 minutes before a meal was 65 mg/dL compared to 64 mg/dL for regular human insulin injected 30 minutes before a meal (see Figure 1A), and 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1B). The maximum blood glucose excursion for APIDRA injected 15 minutes after the start of a meal was 85 mg/dL compared to 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1C).

Figure 1: Serial mean blood glucose collected up to 6 hours following a single dose of APIDRA and regular human insulin. APIDRA given 2 minutes (APIDRA - pre) before the start of a meal compared to regular human insulin given 30 minutes (Regular - 30 min) before start of the meal (see Figure 1A) and compared to regular human insulin (Regular - pre) given 2 minutes before a meal (see Figure 1B). APIDRA given 15 minutes (APIDRA - post) after start of a meal compared to regular human insulin (Regular - pre) given 2 minutes before a meal (see Figure 1C). On the x-axis, zero (0) is the start of a 15-minute meal.

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In a randomized, open-label, two-way crossover study, 16 healthy male subjects received an intravenous infusion of APIDRA or regular human insulin with saline diluent at a rate of 0.8 milliunits/kg/min for two hours. Infusion of the same dose of APIDRA or regular human insulin produced equivalent glucose disposal at steady state.

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 that of regular human insulin.

In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120 minutes) and the peak concentration (Cmax) was 83 microunits/mL (range 40 to 131 microunits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239 minutes) and a Cmax of 50 microunits/mL (range 35 to 71 microunits/mL) for regular human insulin (see Figure 2).

Figure 2: Pharmacokinetic Profiles of Insulin Glulisine and Regular Human Insulin in Patients with Type 1 Diabetes after a Dose of 0.15 units/kg.

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Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.2 units/kg in a euglycemic clamp study in patients with type 2 diabetes (n=24) and a body mass index (BMI) between 20 and 36 kg/m2. The median time to maximum concentration (Tmax) was 100 minutes (range 40 to 120 minutes) and the median peak concentration (Cmax) was 84 microunits/mL (range 53 to 165 microunits/mL) for insulin glulisine compared to a median Tmax of 240 minutes (range 80 to 360 minutes) and a median Cmax of 41 microunits/mL (range 33 to 61 microunits/mL) for regular human insulin (see Figure 3).

Figure 3: Pharmacokinetic Profiles of Insulin Glulisine and Regular Human Insulin in Patients with Type 2 Diabetes after a Subcutaneous Dose of 0.2 units/kg.

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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 approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%).

In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the syringe) and following separate simultaneous subcutaneous injections. There was 27% attenuation of the maximum concentration (Cmax) of APIDRA after premixing; however, the time to maximum concentration (Tmax) was not affected.

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 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.

Specific Populations

Pediatric patients

The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin were assessed in a study conducted in children 7 to 11 years old (n=10) and adolescents 12 to 16 years old (n=10) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics between APIDRA and regular human insulin in these patients with type 1 diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.

Race

A study in 24 healthy Caucasians and Japanese subjects compared the pharmacokinetics and pharmacodynamics 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(0–1h) to AUC(0–clamp end) than Caucasians (21%) although the total exposures were similar. There were similar findings with insulin lispro and regular human insulin.

Obesity

Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.3 units/kg in a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass index (BMI) between 30 and 40 kg/m2. The median time to maximum concentration (Tmax) was 85 minutes (range 49 to 150 minutes) and the median peak concentration (Cmax) was 192 microunits/mL (range 98 to 380 microunits/mL) for insulin glulisine compared to a median Tmax of 150 minutes (range 90 to 240 minutes) and a median Cmax of 86 microunits/mL (range 43 to 175 microunits/mL) for regular human insulin.

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) (see Figure 4).

Figure 4: Glucose Infusion Rates (GIR) in a Euglycemic Clamp Study after Subcutaneous Injection of 0.3 units/kg of APIDRA, Insulin Lispro or Regular Human Insulin in an Obese Population.

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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 with normal renal function (ClCr >80 mL/min), moderate renal impairment (30–50 mL/min), and severe renal impairment (<30 mL/min), the subjects with moderate and severe renal impairment had increased exposure to insulin glulisine by 29% to 40% and reduced clearance of insulin glulisine by 20% to 25% compared to subjects with normal renal function [see Use in Specific Populations (8.6)].

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure [see Use in Specific Populations (8.7)].

Gender

The effect of gender on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

Smoking

The effect of smoking on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

Nonclinical Toxicology

carcinogenesis, mutagenesis, impairment of fertility

Long-term carcinogenicity studies in animals have not been performed. In Sprague Dawley rats, a 12-month study was conducted with insulin glulisine at subcutaneous doses of 2.5, 5, 20 or 50 units/kg administered twice daily, resulting in an exposure 1, 2, 8, and 20 times the average human dose, based on body surface area.

There was a non-dose dependent higher incidence of mammary gland tumors in female rats administered insulin glulisine compared to untreated controls. The incidence of mammary tumors for insulin glulisine and regular human insulin was similar. Insulin glulisine was not mutagenic in the following tests: Ames test, in vitro mammalian chromosome aberration test in V79 Chinese hamster cells, and in vivo mammalian erythrocyte micronucleus test in rats.

In fertility studies in male and female rats at subcutaneous doses up to 10 units/kg/day (2 times the average human dose, based on body surface area comparison), no clear adverse effects on male and female fertility, or general reproductive performance of animals were observed.

Clinical Studies

The safety and efficacy of APIDRA was studied in adult patients with type 1 and type 2 diabetes (n=1833) and in pediatric patients (4 to 17 years) with type 1 diabetes (n=572). The primary efficacy parameter in these trials was glycemic control, assessed using glycated hemoglobin (GHb reported as HbA1c equivalent).

type 1 diabetes-adults

A 26-week, randomized, open-label, active-controlled, non-inferiority 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. Insulin glargine was administered once daily in the evening as the basal insulin. There was a 4-week run-in period with insulin lispro and insulin glargine prior to randomization. Most patients were Caucasian (97%). Fifty eight percent of the patients were men. The mean age was 39 years (range 18 to 74 years). Glycemic control, the number of daily short-acting insulin injections and the total daily doses of APIDRA and insulin lispro were similar in the two treatment groups (see Table 7).

Table 7: Type 1 Diabetes Mellitus–Adult
Treatment duration
Treatment in combination with:
26 weeks
Insulin glargine
APIDRA Insulin Lispro
Glycated hemoglobin (GHb)
GHb reported as HbA1c equivalent

(%)
  Number of patients


331

322
  Baseline mean 7.6 7.6
  Adjusted mean change from baseline -0.1 -0.1
    Treatment difference: APIDRA – Insulin Lispro 0.0
    95% CI for treatment difference (-0.1; 0.1)
Basal insulin dose (Units/day)
  Baseline mean 24 24
  Adjusted mean change from baseline 0 2
Short-acting insulin dose (Units/day)
  Baseline mean 30 31
  Adjusted mean change from baseline -1 -1
Mean number of short-acting insulin injections per day 3 3
Body weight (kg)
  Baseline mean 73.9 74.1
  Mean change from baseline 0.6 0.3

type 2 diabetes-adults

A 26-week, randomized, open-label, active-controlled, non-inferiority 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 with regular human insulin and NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The mean age was 58 years (range 26 to 84 years). The average body mass index (BMI) was 34.6 kg/m2. At randomization, 58% of the patients were taking an oral antidiabetic agent. These patients were instructed to continue use of their oral antidiabetic agent at the same dose throughout the trial. The majority of patients (79%) mixed their short-acting insulin with NPH human insulin immediately prior to injection. The reductions from baseline in GHb were similar between the 2 treatment groups (see Table 8). 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 8).

Table 8: Type 2 Diabetes Mellitus–Adult
Treatment duration
Treatment in combination with:
26 weeks
NPH human insulin
APIDRA Regular Human Insulin
Glycated hemoglobin (GHb)
GHb reported as HbA1c equivalent

(%)
  Number of patients


404

403
  Baseline mean 7.6 7.5
  Adjusted mean change from baseline -0.5 -0.3
    Treatment difference: APIDRA – Regular Human Insulin -0.2
    95% CI for treatment difference (-0.3; -0.1)
Basal insulin dose (Units/day)
  Baseline mean 59 57
  Adjusted mean change from baseline 6 6
Short-acting insulin dose (Units/day)
  Baseline mean 32 31
  Adjusted mean change from baseline 4 5
Mean number of short-acting insulin injections per day 2 2
Body weight (kg)
  Baseline mean 100.5 99.2
  Mean change from baseline 1.8 2.0

type 1 diabetes-adults: pre & post meal administration

A 12-week, randomized, open-label, active-controlled, non-inferiority 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. Insulin glargine was administered once daily at bedtime as the basal insulin. There was a 4-week run-in period with regular human insulin and insulin glargine followed by randomization. Most patients were Caucasian (94%). The mean age was 40 years (range 18 to 73 years). Glycemic control (see Table 9) was comparable for the 3 treatment regimens. No changes from baseline between the treatments were seen in the total daily number of short-acting insulin injections (see Table 9).

Table 9: Pre and Post Meal Administration in Type 1 Diabetes Mellitus - Adult
Treatment duration
Treatment in combination with:
12 weeks
insulin glargine
12 weeks
insulin glargine
12 weeks
insulin glargine
APIDRA pre meal APIDRA post meal Regular Human Insulin
Glycated hemoglobin (GHb)
GHb reported as HbA1c equivalent

(%)
  Number of patients


268

276

257
  Baseline mean 7.7 7.7 7.6
  Adjusted mean change from baseline
Adjusted mean change from baseline treatment difference (98.33% CI for treatment difference):
  APIDRA pre meal vs Regular Human Insulin -0.1 (-0.3; 0.0)
  APIDRA post meal vs Regular Human Insulin 0.0 (-0.1; 0.2)
  APIDRA post meal vs pre meal 0.2 (0.0; 0.3)
-0.3 -0.1 -0.1
Basal insulin dose (Units/day)
  Baseline mean 29 29 28
  Adjusted mean change from baseline 1 0 1
Short-acting insulin dose (Units/day)
  Baseline mean 29 29 27
  Adjusted mean change from baseline -1 -1 2
Mean number of short-acting insulin injections per day 3 3 3
Body weight (kg)
  Baseline mean 79.2 80.3 78.9
  Mean change from baseline 0.3 -0.3 0.3

type 1 diabetes-pediatric patients

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in children and adolescents older than 4 years of age with type 1 diabetes mellitus to assess the safety and efficacy of APIDRA (n=277) compared to insulin lispro (n=295) when administered subcutaneously within 15 minutes before a meal. Patients also received insulin glargine (administered once daily in the evening) or NPH insulin (administered once in the morning and once in the evening). There was a 4-week run-in period with insulin lispro and insulin glargine or NPH prior to randomization. Most patients were Caucasian (91%). Fifty percent of the patients were male. The mean age was 12.5 years (range 4 to 17 years). Mean BMI was 20.6 kg/m2. Glycemic control (see Table 10) was comparable for the two treatment regimens.

Table 10: Results from a 26-Week Study in Pediatric Patients with Type 1 Diabetes Mellitus
APIDRA Lispro
Number of patients 271 291
Basal Insulin NPH or insulin glargine NPH or insulin glargine
Glycated hemoglobin (GHb)
GHb reported as HbA1c equivalent

(%)

  Baseline mean 8.2 8.2
  Adjusted mean change from baseline 0.1 0.2
  Treatment Difference: Mean (95% confidence interval) -0.1 (-0.2, 0.1)
Basal insulin dose (Units/kg/day)
  Baseline mean 0.5 0.5
  Mean change from baseline 0.0 0.0
Short-acting insulin dose (Units/kg/day)
  Baseline mean 0.5 0.5
  Mean change from baseline 0.0 0.0
Mean number of short-acting insulin injections per day 3 3
Baseline mean body weight (kg)
Mean weight change from baseline (kg)
51.5
2.2
50.8
2.2

type 1 diabetes-adults: continuous subcutaneous insulin infusion

A 12-week randomized, active control study (APIDRA versus insulin aspart) conducted in adults with type 1 diabetes (APIDRA n=29, insulin aspart n=30) evaluated the use of APIDRA in an external continuous subcutaneous insulin pump. All patients were Caucasian. The mean age was 46 years (range 21 to 73 years). The mean GHb increased from baseline to endpoint in both treatment groups (from 6.8% to 7.0% for APIDRA; from 7.1% to 7.2% for insulin aspart).

This drug label information is as submitted to the Food and Drug Administration (FDA) and is intended for informational purposes only. If you think you may have a medical emergency, immediately call your doctor or dial 911. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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