Absorption and Bioavailability — Studies in healthy volunteers and patients with diabetes demonstrated that Insulin Lispro is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Insulin Lispro 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 Insulin Lispro and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa. 

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

Insulin Lispro 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 Insulin Lispro 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 Insulin Lispro 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 — When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of Insulin Lispro appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively). 

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

Elimination — After subcutaneous administration of Insulin Lispro, the t1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Insulin Lispro and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, Insulin Lispro demonstrated a mean t1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses. 

Specific Populations

The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of Insulin Lispro have not been studied. 

Renal Impairment — Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and Insulin Lispro. 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 [see Use in Specific Populations (8.6)].

Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of Insulin Lispro 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 [see Use in Specific Populations (8.7)].