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Mechanism of Action

Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. 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

HUMALOG has been shown to be equipotent to human insulin on a molar basis. One unit of HUMALOG has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that HUMALOG has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.

The time course of action of insulin and insulin analogs, such as HUMALOG, may vary considerably in different individuals or within the same individual. The parameters of HUMALOG activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see WARNINGS AND PRECAUTIONS].

Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes.^a

^a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.

Pharmacokinetics

Absorption and Bioavailability

Studies in healthy volunteers and patients with diabetes demonstrated that HUMALOG is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of HUMALOG ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes (see Figure 2).

Figure 2: Serum HUMALOG and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes.^a

^a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.

HUMALOG was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After HUMALOG was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of HUMALOG is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.

Distribution

After subcutaneous administration, the volume of distribution for HUMALOG is identical to that of regular human insulin, with a range of 0.26 to 0.36 L/kg. When administered intravenously, the volume of distribution of HUMALOG (range of 0.26 to 0.36 L/kg) was similar to that of regular human insulin (range of 0.32 to 0.67 L/kg).

Metabolism

Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of HUMALOG is identical to that of regular human insulin.

Elimination

After subcutaneous administration of HUMALOG, the t½ is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, HUMALOG and regular human insulin demonstrated similar dose-dependent elimination, with a t½ of 0.44 hours (26 min) and 0.34 hours (20 min), respectively (0.1 unit/kg dose) and 0.86 hours (52 min) and 1.1 hours (66 min), respectively (0.2 unit/kg dose).

Specific Populations

Age — The effect of age on the pharmacokinetics of HUMALOG has not been studied. However, in large clinical trials, subgroup analysis based on age did not indicate any difference in postprandial glucose parameters between HUMALOG and regular human insulin.

Gender — The effect of gender on the pharmacokinetics of HUMALOG has not been studied. However, in large clinical trials, sub-group analysis based on gender did not indicate any difference in postprandial glucose parameters between HUMALOG and regular human insulin.

Renal Impairment — Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and HUMALOG. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with renal dysfunction [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetic of HUMALOG as compared to patients with no hepatic dysfunction. However, 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 HUMALOG, may be necessary in patients with hepatic dysfunction.

Race – The effects of race on the pharmacokinetics and pharmacodynamics of HUMALOG have not been studied.

Obesity – The effect of obesity on the pharmacokinetics and pharmacodynamics of HUMALOG has not been studied.

Pregnancy – The effect of pregnancy on the pharmacokinetics and pharmacodynamics of HUMALOG has not been studied [see Use In Specific Populations].

Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of HUMALOG has not been studied.

Animal Toxicology and /or Pharmacology

In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin.

Clinical Studies

The safety and efficacy of HUMALOG were studied in children, adolescent, and adult patients with type 1 diabetes (n=789) and adult patients with type 2 diabetes (n=722).

Type 1 Diabetes — Adults and Adolescents

A 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type 1 diabetes to assess the safety and efficacy of HUMALOG (n=81) compared with Humulin® R [REGULAR insulin human injection, USP (rDNA origin)] (n=86). HUMALOG was administered by subcutaneous injection immediately prior to meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® U [ULTRALENTE® human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was a 2- to 4-week run-in period with Humulin R and Humulin U before randomization. Most patients were Caucasian (97%). Forty-seven percent of the patients were male. The mean age was 31 years (range 12 to 70 years). Glycemic control, the total daily doses of HUMALOG and Humulin R, and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar in the two treatment groups. There were no episodes of diabetic ketoacidosis in either treatment group.

Table 4: Type 1 Diabetes Mellitus – Adults and Adolescents

Type 2 Diabetes – Adults

A 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type 2 diabetes (n=722) to assess the safety and efficacy of HUMALOG for 3 months followed by Humulin R for 3 months or the reverse sequence. HUMALOG was administered by subcutaneous injection immediately before meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® N [NPH human insulin (rDNA origin) isophane suspension] or Humulin U was administered once or twice daily as the basal insulin. All patients participated in a 2-to 4-week run-in period with Humulin R and Humulin N or Humulin U. Most of the patients were Caucasian (88%), and the numbers of men and women in each group were approximately equal. The mean age was 58.6 years (range 23.8 to 85 years). The average body mass index (BMI) was 28.2 kg/m². During the study, the majority of patients used Humulin N (84%) compared with Humulin U (16%) as their basal insulin. The reductions from baseline in HbA1c and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar between the two treatments from the combined groups (see Table 5).

Table 5: Type 2 Diabetes Mellitus — Adults

Type 1 Diabetes – Pediatric and Adolescents

An 8-month, crossover study of adolescents with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: HUMALOG or Humulin R, both administered with Humulin N (NPH human insulin) as the basal insulin. HUMALOG achieved glycemic control comparable to Humulin R, as measured by HbA1c (see Table 6), and both treatment groups had a comparable incidence of hypoglycemia. In a 9-month, crossover study of prepubescent children (n=60) with type 1 diabetes, aged 3 to 11 years, HUMALOG administered immediately before meals, HUMALOG administered immediately after meals and Humulin R administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA1c, and incidence of hypoglycemia, regardless of treatment group.

Table 6: Pediatric Subcutaneous Administration of HUMALOG in Type 1 Diabetes

Type 1 Diabetes – Adults Continuous Subcutaneous Insulin Infusion

To evaluate the administration of HUMALOG via external insulin pumps, two open-label, crossover design studies were performed in patients with type 1 diabetes. One study involved 39 patients, ages 19 to 58 years, treated for 24 weeks with HUMALOG or regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.8% to 7.2% in the HUMALOG-treated patients and from 7.8% to 7.5% in the regular human insulin-treated patients. Another study involved 60 patients (mean age 39, range 15 to 58 years) treated for 24 weeks with either HUMALOG or buffered regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.7% to 7.4% in the HUMALOG-treated patients and remained unchanged from 7.7% in the buffered regular human insulin-treated patients. Rates of hypoglycemia were comparable between treatment groups in both studies.

Type 1 Diabetes – Pediatric Continuous Subcutaneous Insulin Infusion

A randomized, 16-week, open-label, parallel design, study of children and adolescents with type 1 diabetes (n=298) aged 4 to 18 years compared two subcutaneous infusion regimens administered via an external insulin pump: insulin aspart (n=198) or HUMALOG (n=100). These two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of hypoglycemia after 16 weeks of treatment (see Table 7). Infusion site reactions were similar between groups.

Table 7: Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)

Last reviewed on RxList: 6/3/2011
This monograph has been modified to include the generic and brand name in many instances.