Humalog (Insulin Lispro (Rdna Origin)) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Antidiabetic Activity-- The primary activity of insulin, including Humalog, is the regulation of glucose metabolism. In addition, all insulins have several anabolic and anti-catabolic actions on many tissues in the body. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the conversion of excess glucose into fat.

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 human regular insulin, but its effect is more rapid and of shorter duration. The glucose-lowering activity of Humalog and human regular insulin is comparable when administered to normal volunteers by the intravenous route.

PHARMACOKINETICS-

Absorption and Bioavailability-- Humalog is as bioavailable as human regular insulin, with absolute bioavailability ranging between 55%-77% with doses between 0.1-0.2 U/kg, inclusive. Studies in normal volunteers and patients with type 1 (insulin-dependent) diabetes demonstrated that Humalog is absorbed faster than human regular insulin (U-100) (Figure 2). In normal volunteers given subcutaneous doses of Humalog ranging from 0.1-0.4 U/kg, peak serum levels were seen 30-90 minutes after dosing. When normal volunteers received equivalent doses of human regular insulin, peak insulin levels occurred between 50-120 minutes after dosing. Similar results were seen in patients with type 1 diabetes. The pharmacokinetic profiles of Humalog and human regular insulin are comparable to one another when administered to normal volunteers by the intravenous route. Humalog was absorbed at a consistently faster rate than human regular insulin in healthy male volunteers given 0.2 U/kg human regular insulin or Humalog at abdominal, deltoid, or femoral subcutaneous sites, the three sites often used by patients with diabetes. After abdominal administration of Humalog, serum drug levels are higher and the duration of action is slightly shorter than after deltoid or thigh administration (see DOSAGE AND ADMINISTRATION). Humalog has less intra- and inter-patient variability compared to human regular insulin.

Distribution-- The volume of distribution for Humalog is identical to that of human regular insulin, with a range of 0.26-0.36 L/kg.

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

Elimination-- When Humalog is given subcutaneously, its t_1/2 is shorter than that of human regular insulin (1 vs 1.5 hours, respectively). When given intravenously, Humalog and human regular insulin show identical dose-dependent elimination, with a t_1/2 of 26 and 52 minutes at 0.1 U/kg and 0.2 U/kg, respectively.

Pharmacodynamics-- Studies in normal volunteers and patients with diabetes demonstrated that Humalog has a more rapid onset of glucose-lowering activity, an earlier peak for glucose lowering, and a shorter duration of glucose-lowering activity than human regular insulin (Figure 3). The earlier onset of activity of Humalog is directly related to its more rapid rate of absorption. 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 3 should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables (see PRECAUTIONS, General).

In open-label, crossover studies of 1008 patients with type 1 diabetes and 722 patients with type 2 (non-insulin-dependent) diabetes, Humalog reduced postprandial glucose compared with human regular insulin (see Table 1). The clinical significance of improvement in postprandial hyperglycemia has not been established.

In 12-month parallel studies in patients with type 1 and type 2 diabetes, HbA_lc did not differ between patients treated with human regular insulin and those treated with Humalog.

Hypoglycemia-- While the overall rate of hypoglycemia did not differ between patients with type 1 and type 2 diabetes treated with Humalog compared with human regular insulin, patients with type 1 diabetes treated with Humalog had fewer hypoglycemic episodes between midnight and 6 a.m. The lower rate of hypoglycemia in the Humalog-treated group may have been related to higher nocturnal blood glucose levels, as reflected by a small increase in mean fasting blood glucose levels.

Humalog in Combination with Sulfonylurea Agents-- In a two-month study in patients with fasting hyperglycemia despite maximal dosing with sulfonylureas (SU), patients were randomized to one of three treatment regimens; Humulin NPH at bedtime plus SU, Humalog three times a day before meals plus SU, or Humalog three times a day before meals and Humulin NPH at bedtime. The combination of Humalog and SU resulted in an improvement in HbA_lc accompanied by a weight gain (see Table 2).

Special Populations--

Age and Gender-- Information on the effect of age and gender on the pharmacokinetics of Humalog is unavailable. However, in large clinical trials, subgroup analysis based on age and gender did not indicate any difference in postprandial glucose parameters between Humalog and human regular insulin.

Smoking-- The effect of smoking on the pharmacokinetics and glucodynamics of Humalog has not been studied.

Pregnancy-- The effect of pregnancy on the pharmacokinetics and glucodynamics of Humalog has not been studied.

Obesity-- The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and glucodynamics of Humalog has not been studied. In large clinical trials, which included patients with Body Mass Index up to and including 35 kg/m² no consistent differences were seen between Humalog and Humulin R with respect to postprandial glucose parameters.

Renal Impairment-- Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study of 25 patients with type 2 diabetes and a wide range of renal function, the pharmacokinetic differences between Humalog and human regular insulin were generally maintained. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary in patients with renal dysfunction.

Hepatic Impairment-- Some studies with human insulin have shown increased circulating levels of insulin in patients with hepatic failure. In a study of 22 patients with type 2 diabetes, impaired hepatic function did not affect the subcutaneous absorption or general disposition of Humalog when compared to patients with no history of hepatic dysfunction. In that study, Humalog maintained its more rapid absorption and elimination when compared to human regular insulin. Careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary in patients with hepatic dysfunction.