Exubera System

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Exubera is the first Food and Drug Administration approved inhaled insulin product. It is approved for the treatment of adult patients with T1DM and T2DM (22). Exubera is currently available in a short acting formulation to control post prandial glucose excursions. In patients with T1DM, Exubera should be used in combination with long acting insulin, which provides basal insulin replacement. In patients with T2DM, Exubera can be used either as monotherapy or in combination with long acting insulin or insulin sensitizers. The delivery system administers a dry-powder through a device that provides a spacer into which particles are launched via a compressed air supply then slowly inhaled by the patient (Fig. 1). The spacer helps decouple the high speed of the jet needed to disaggregate particles from particle impaction in the back of the oropharnx. The aerosolized powder is contained in blister packets which are administered through the inhaler. Each blister pack contains either 1 or 3mg of insulin. The 1-mg blister pack is equivalent to approximately 3 units of SC insulin and the 3-mg blister pack is equivalent to approximately 8 units. The Exubera system is designed to emit a specific dose of insulin from the mouthpiece (Table 2). Up to 45% of the 1-mg blister contents and 25% of the 3-mg blister contents may be retained within the blister well. Patients must take great care in dosing insulin with the Exubera system since three 1-mg blister packs do not equal one 3-mg blister pack. Three 1-mg blister packs have a 30-40% higher Cmax and area under the curve (AUC) compared to one 3-mg blister pack (22).

In patients with diabetes, the serum insulin concentrations peak faster with Exubera (49 min, range 30-90 min) than SC regular insulin (105 min, range 60-240 min; Fig. 2) (22). In healthy volunteers, the onset of glucose lowering activity occurs in 31 min with the maximum glucose lowering effect occurring at approximately 110 min. The duration of action is 6h, which is longer than that of SC insulin lispro and comparable to SC regular insulin (23). In another study in 17 healthy male volunteers, Exubera's® time action profile was compared to SC insulin lispro and SC regular insulin using the

Figure 1 Exúbera inhaler.

euglycemic insulin clamp method (24). When compared to SC regular insulin, Exubera had a faster onset of action (32 vs. 48 min, respectively; P=0.001). The same could be said when Exubera was compared to SC insulin lispro (32 vs. 41min, respectively; P<0.05). The time to maximal

Table 2 Exubera Emitted Dosing Information

Fill mass*

Nominal dose

Emitted dose**a,c

Fine particle dose**b,c

1.7

1.0

0.53

0.4

5.1

3.0

2.03

l.G

*mg of powder; **mg of insulin. aFlow rate of 30L/min for 2.5 s. bFlow rate of 28.3 L/min for 3 s.

"Emitted dose and fine particle dose information are not intended to predict actual pharmacodynamic response.

*mg of powder; **mg of insulin. aFlow rate of 30L/min for 2.5 s. bFlow rate of 28.3 L/min for 3 s.

"Emitted dose and fine particle dose information are not intended to predict actual pharmacodynamic response.

O 60 120 180 240 300 360 420 48C

Time (min)

Figure 2 Change from baseline in free serum insulin concentration in healthy, non-diabetic subjects who received a single dose of Exubera® (6 mg) and a single dose of SC regular insulin (18 units) on separate days.

O 60 120 180 240 300 360 420 48C

Time (min)

Figure 2 Change from baseline in free serum insulin concentration in healthy, non-diabetic subjects who received a single dose of Exubera® (6 mg) and a single dose of SC regular insulin (18 units) on separate days.

metabolic effect was comparable between Exubera and SC insulin lispro (143 vs. 137 min; P = NS) but was shorter compared to SC regular insulin (193 min; P<0.01). The duration of metabolic activity for Exubera was similar to SC insulin regular, but significantly longer than SC insulin lispro.

Exubera's insulin pharmacokinetic and glucokinetic reproducibility have been investigated in two studies (25,26). The reproducibility of Exubera was similar to SC regular insulin and the intrasubject differences between the two same-dose route of administration were small.

Special Populations and Influence of Absorption

Underlying lung disease: Exubera has not been studied in certain patient populations such as diabetic patients with asthma or chronic obstructive pulmonary disease (COPD). Since it has not been studied, the use of Exubera in these patients is not recommended. When studied in non-diabetic patients with COPD, the plasma insulin levels were twice those in subjects without COPD (22).

Smoking: Smoking increases insulin levels by more than two times compared to non-smokers. Therefore, it is recommended that patients who smoke or have stopped smoking in the previous 6 months not receive Exubera. Within 1 week of discontinuation of smoking the bioavailability of Exubera decreased by approximately 50% when compared to smokers, but was still higher than non-smokers. These rapid changes in absorption make dose prediction, and the potential risk of hypoglycemia, higher in smokers (22,27).

Asthma: Asthma can greatly affect the ability to move air and thus deliver particles to the deep lung. Studies have consistently reported reductions (approximately 20%) in absorption of inhaled insulin in subjects with mild to moderate asthma when compared to subjects without asthma. Additionally, bronchodilator therapy, if administered prior to inhaled insulin therapy, can increase absorption by 25-50%. These large absorption differences are the basis for the current recommendation against inhaled insulin use in subjects with asthma (22).

Intercurrent respiratory tract illness: Clinically, concurrent, uncomplicated upper respiratory illnesses (bronchitis, upper respiratory infection, and rhinitis) did not affect rates of glycemic control or hypoglycemia (22). About 1 in the 20 subjects temporarily discontinued Exubera therapy during the illness and alternative therapy would have to be implemented in these subjects (2).

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