Mechanism of Action
The primary activity of insulin is regulation of glucose metabolism. Insulin lowers blood glucose concentrations by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.
EXUBERA delivers insulin by oral inhalation. The insulin is absorbed as quickly as subcutaneously administered rapid-acting insulin analogs and more quickly than subcutaneously administered regular human insulin in healthy subjects and in patients with type 1 or type 2 diabetes (see Figure 1).
Figure 1: Mean Changes in Free Insulin Serum Concentrations (µU/mL) in Patients with Type 2 Diabetes Following Administration of Single Doses of Inhaled Insulin from EXUBERA (6 mg) and Subcutaneous Regular Human Insulin (18U)
In clinical studies in patients with type 1 and type 2 diabetes, after inhalation of EXUBERA, serum insulin reached peak concentration more quickly than after subcutaneous injection of regular human insulin, 49 minutes (range 30 to 90 minutes) compared to 105 minutes (range 60 to 240 minutes), respectively.
In clinical studies, the absorption of subcutaneous regular human insulin declined with increasing patient body mass index (BMI). However, the absorption of insulin following inhalation of EXUBERA was independent of BMI.
In a study in healthy subjects, systemic insulin exposure (AUC and Cmax) following administration of EXUBERA increased with dose over a range of 1 to 6 mg when administered as combinations of 1 and 3 mg blisters.
In a study where the dosage form of three 1 mg blisters was compared with one 3 mg blister, Cmax and AUC after administration of three 1 mg blisters were approximately 30% and 40% greater, respectively, than that after administration of one 3 mg blister (see DOSAGE AND ADMINISTRATION).
Distribution and Elimination
Because recombinant human insulin is identical to endogenous insulin, the systemic distribution and elimination are expected to be the same. However, this has not been confirmed for EXUBERA.
EXUBERA, like subcutaneously administered rapid-acting insulin analogs, has a more rapid onset of glucose-lowering activity than subcutaneously administered regular human insulin. In healthy volunteers, the duration of glucose-lowering activity for EXUBERA was comparable to subcutaneously administered regular human insulin and longer than subcutaneously administered rapid-acting insulin analogs (see Figure 2).
Figure 2. Mean Glucose Infusion Rate (GIR) Normalized to GIRmax for Each Subject Treatment Versus Time in Healthy Volunteers
*Determined as amount of glucose infused to maintain constant plasma glucose concentrations, normalized to maximum values (percent of maximum values); indicative of insulin activity.
When EXUBERA is inhaled, the onset of glucose-lowering activity in healthy volunteers occurs within 10–20 minutes. The maximum effect on glucose lowering is exerted approximately 2 hours after inhalation. The duration of glucose-lowering activity is approximately 6 hours.
In patients with type 1 or type 2 diabetes, EXUBERA has a greater glucose-lowering effect within the first two hours after dosing when compared with subcutaneously administered regular human insulin.
The intra-subject variability of glucose-lowering activity of EXUBERA is generally comparable to that of subcutaneously administered regular human insulin in patients with type 1 and 2 diabetes.
In children (6–11 years) and adolescents (12–17 years) with type 1 diabetes, time to peak insulin concentration for EXUBERA was achieved faster than for subcutaneous regular human insulin, which is consistent with observations in adult patients with type 1 diabetes.
There are no apparent differences in the pharmacokinetic properties of EXUBERA when comparing patients over the age of 65 years and younger adult patients.
In subjects with and without diabetes, no apparent differences in the pharmacokinetic properties of EXUBERA were observed between men and women.
A study was performed in 25 healthy Caucasian and Japanese non-diabetic subjects to compare the pharmacokinetic and pharmacodynamic properties of EXUBERA, versus subcutaneous injection of regular human insulin. The pharmacokinetic and pharmacodynamic properties of EXUBERA were comparable between the two populations.
The absorption of EXUBERA is independent of patient BMI.
The effect of renal impairment on the pharmacokinetics of EXUBERA has not been studied. Careful glucose monitoring and dose adjustments of insulin may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment).
The effect of hepatic impairment on the pharmacokinetics of EXUBERA has not been studied. Careful glucose monitoring and dose adjustments of insulin may be necessary in patients with hepatic dysfunction (see PRECAUTIONS, Hepatic Impairment).
The absorption of EXUBERA in pregnant patients with gestational and pre-gestational type 2 diabetes was consistent with that in non-pregnant patients with type 2 diabetes (see PRECAUTIONS, Pregnancy).
In smokers, the systemic insulin exposure for EXUBERA is expected to be 2 to 5 fold higher than in non-smokers. EXUBERA is contraindicated in patients who smoke or who have discontinued smoking less than 6 months prior to starting EXUBERA therapy. If a patient starts or resumes smoking, EXUBERA must be discontinued immediately due to the increased risk of hypoglycemia, and an alternative treatment must be utilized (see CONTRAINDICATIONS).
In clinical studies of EXUBERA in 123 patients (69 of whom were smokers), smokers experienced a more rapid onset of glucose-lowering action, greater maximum effect, and a greater total glucose-lowering effect (particularly during the first 2–3 hours after dosing), compared to non-smokers.
Passive Cigarette Smoke
In contrast to the increase in insulin exposure following active smoking, when EXUBERA was administered to 30 healthy non-smoking volunteers following 2 hours of exposure to passive cigarette smoke in a controlled experimental setting, insulin AUC and Cmax were reduced by approximately 20% and 30%, respectively. The pharmacokinetics of EXUBERA have not been studied in nonsmokers who are chronically exposed to passive cigarette smoke.
Patients with Underlying Lung Diseases
The use of EXUBERA in patients with underlying lung disease, such as asthma or COPD, is not recommended because the safety and efficacy of EXUBERA in this population have not been established (see WARNINGS). The use of EXUBERA is contraindicated in patients with unstable or poorly controlled lung disease, because of wide variations in lung function that could affect the absorption of EXUBERA and increase the risk of hypoglycemia or hyperglycemia (see CONTRAINDICATIONS).
In a pharmacokinetic study in 24 non-diabetic subjects with mild asthma, the absorption of insulin following administration of EXUBERA, in the absence of treatment with a bronchodilator, was approximately 20% lower than the absorption seen in subjects without asthma. However, in a study in 24 non-diabetic subjects with Chronic Obstructive Pulmonary Disease (COPD), the systemic exposure following administration of EXUBERA was approximately two-fold higher than that in normal subjects without COPD (see PRECAUTIONS, Underlying Lung Disease).
Administration of albuterol 30 minutes prior to administration of EXUBERA in non-diabetic subjects with both mild asthma (n=36) and moderate asthma (n=31) resulted in a mean increase in insulin AUC and Cmax of between 25 and 50% compared to when EXUBERA was administered alone (see PRECAUTIONS, Drug Interactions).