Humalog (Page 3 of 6)

12.3 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
(click image for full-size original)

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 t1/2 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 t1/2 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, sub-group 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 (5.5)].

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 (8.1)].

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose.

Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays.

Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.16, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

13.2 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.

14 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).

14.1 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

a Values are Mean ± SD

b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.

Treatment DurationTreatment in Combination with: 12 monthsHumulin U
HUMALOG Humulin R
N 81 86
Baseline HbA1c (%)a 8.2 ± 1.4 8.3 ± 1.7
Change from baseline HbA1c (%)a -0.1 ± 0.9 0.1 ± 1.1
Treatment Difference in HbA1c Mean (95% confidence interval) 0.4 (0.0, 0.8)
Baseline short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1
End-of-Study short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1
Change from baseline short-acting insulin dose (units/kg/day) -0.0 ± 0.1 0.0 ±0.1
Baseline Body weight (kg) 72 ± 12.7 71 ± 11.3
Weight change from baseline (kg) 1.4 ± 3.6 1.0 ± 2.6
Patients with severe hypoglycemia (n, %)b 14 (17%) 18 (21%)

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