Pulmonary Insulin Administration Using the AERx® System: Physiological and Physicochemical Factors Influencing Insulin Effectiveness in Healthy Fasting Subjects

Farr, Stephen J.; McElduff, Aidan; Mather, Laurence E.; Okikawa, Jerry; Ward, Michael E.; Gonda, Igor; Ličko, Vojtech; Rubsamen, Reid M.

doi:10.1089/15209150050025131

Cited by 70 publications

(40 citation statements)

References 20 publications

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“…There was no effect of dose on T GIRmax for inhaled or subcutaneously injected insulin. The mean relative biopotency for inhaled insulin (95% CI) at the low, medium, and high doses was 13% (11)(12)(13)(14), 16% (13-18), and 16% (14 -18), respectively. There was no significant difference in relative biopotency for inhaled insulin among the dose studies, as indicated by overlapping 95% CIs.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Dose-Response Relationships of Inhaled Insulin Delivered via the Aerodose Insulin Inhaler and Subcutaneously Injected Insulin in Patients With Type 2 Diabetes

et al. 2003

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OBJECTIVE -To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36 -80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h.RESULTS -Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (T max 77 Ϯ 66 vs. 193 Ϯ 104 min, P Ͻ 0.001) and time-to-peak metabolic effects (T GIRmax 240 Ϯ 94 vs. 353 Ϯ 60 min, P Ͻ 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P ϭ 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed.CONCLUSIONS -The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection. Diabetes Care 26:2842-2847, 2003D emonstrating that inhaled insulin can be titrated similar to subcutaneous injection is an important prerequisite to showing the clinical viability of this novel mode of insulin delivery. Although several specialized aerosol delivery systems are currently in various stages of development for pulmonary delivery of insulin (1-3), a head-to-head comparison of the dose response of inhaled and subcutaneously injected insulin has not been reported. The Aerodose insulin inhaler is developed to deliver aerosolized liquid insulin to meet the preprandial insulin needs of patients with diabetes. The aim of the present study was, therefore, to compare the dose-response relationship of inhaled and subcutaneously injected insulin and to determine the resulting inhalation-to-subcutaneous injection conversion ratio across three doses in patients with type 2 diabetes. RESEARCH DESIGN ANDMETHODS -A single-center, openlabel, randomized, active-controlled, crossover s...

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Section: Pharmacodynamicsmentioning

confidence: 99%

Dose-Response Relationships of Inhaled Insulin Delivered via the Aerodose Insulin Inhaler and Subcutaneously Injected Insulin in Patients With Type 2 Diabetes

et al. 2003

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“…This alternative is mainly recommended and used in patients with type 1 diabetes. One recent development is that of inhaled insulin systems, and current published data have shown the clinical viability of inhaled insulin in all patients with diabetes (8,9).The AERx insulin diabetes management system (iDMS) addresses factors such as particle size (10) and breathing technique (11,12), which have to be correctly controlled if inhaled insulin is to be clinically feasible. AERx iDMS delivers, from a unique insulin strip, liquid insulin aerosol droplets (1-3 m) to the deep lung, only during precise predefined inspiratory flow and volume (12).…”

mentioning

confidence: 99%

“…The AERx insulin diabetes management system (iDMS) addresses factors such as particle size (10) and breathing technique (11,12), which have to be correctly controlled if inhaled insulin is to be clinically feasible. AERx iDMS delivers, from a unique insulin strip, liquid insulin aerosol droplets (1-3 m) to the deep lung, only during precise predefined inspiratory flow and volume (12).…”

mentioning

confidence: 99%

“…AERx iDMS delivers, from a unique insulin strip, liquid insulin aerosol droplets (1-3 m) to the deep lung, only during precise predefined inspiratory flow and volume (12). The device is designed to ensure insulin delivery only when the breathing technique is optimal (breath check); it also records insulin dose and patient use to allow physicians to track compliance and inhalation technique, thereby improving treatment outcome.…”

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confidence: 99%

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Intensive Therapy With Inhaled Insulin via the AERx Insulin Diabetes Management System

et al. 2004

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OBJECTIVE -To compare the glycemic control of inhaled insulin via the AERx insulin diabetes management system (iDMS) with that of subcutaneous (SC) insulin, both combined with NPH insulin at bedtime, in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -The AERx iDMS uses a liquid insulin formulation to achieve flexible precise mealtime dosing (with increments corresponding to 1 IU administered subcutaneously) and ensures insulin delivery only when the breathing technique is optimal. This trial in patients with type 2 diabetes compared the glycemic control (HbA 1c ) achieved by inhaled insulin administered via AERx iDMS with that using SC insulin. This was a randomized, 12-week, open-label, parallel, multicenter, multinational trial in 107 nonsmoking patients with type 2 diabetes (mean age 59 years, mean duration of diabetes 11.9 years). Patients were randomized to receive either inhaled fast-acting human insulin via AERx iDMS immediately before meals or SC fast-acting human insulin administered 30 min before meals, both in combination with evening NPH insulin.RESULTS -Baseline and demographic characteristics were similar between the two groups. There was no statistically significant difference in HbA 1c between the AERx and SC groups after 12 weeks of treatment (7.84 Ϯ 0.77 vs. 7.76 Ϯ 0.77%, P ϭ 0.60). Fasting serum glucose was significantly lower in the AERx group compared with the SC group by the end of the trial (8.9 Ϯ 3.8 vs. 10.8 Ϯ 3.7 mmol/l, P ϭ 0.01) with a similar NPH dose in the two groups (0.23 vs. 0.23 IU/kg, P ϭ 0.93). There were no statistically significant differences between the two groups in the intra-subject variability of fasting or prandial blood glucose increment. Adverse events were similar in the two groups. No major safety concerns were raised during the trial.CONCLUSIONS -In patients with type 2 diabetes, preprandial inhaled insulin via AERx iDMS is as effective as preprandial SC insulin injection in achieving glycemic control with similar tolerability. Diabetes Care 27:162-167, 2004M any patients with type 2 diabetes initially achieve adequate glycemic control with diet, exercise, and oral antidiabetic medication. However, most patients eventually require exogenous insulin injections to attain glycemic control targets (1). Despite this, patients and physicians appear to be hesitant to use insulin, and, consequently, patients remain in poor glycemic control (2-5). Needle anxiety is one of the factors associated with this reluctance (6,7); therefore, new routes of insulin administration could be used to achieve and maintain optimal glycemic control.Presently, the alternatives to subcutaneous (SC) injections of insulin are limited. The only existing clinical alternative is continuous SC insulin infusion, or insulin administered by means of an implantable pump. This alternative is mainly recommended and used in patients with type 1 diabetes. One recent development is that of inhaled insulin systems, and current published data have shown the clinical viability of inhaled insulin in...

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“…Large tidal volume ventilation after dosing leads to increased absorption of inhaled insulin in rabbits (11), and increased serum levels of inhaled insulin have been reported in humans after performance of pulmonary function test maneuvers, which included deep breathing (12). Increased absorption/absorption rate as an effect of exercise is well known for other inhaled substances such as technetium 99m-labeled diethylene triamine penta-acetic acid (13,14), nedocromil sodium (15), and terbutaline (16).…”

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confidence: 99%

The Effect of Exercise on the Absorption of Inhaled Human Insulin via the AERx Insulin Diabetes Management System in People With Type 1 Diabetes

Petersen

Köhler²,

Korsatko³

et al. 2007

Diabetes Care

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OBJECTIVE -This study investigated the effect of moderate exercise on the absorption of inhaled insulin via the AERx insulin diabetes management system (iDMS). RESEARCH DESIGN AND METHODS -In this randomized, open-label, four-period, crossover, glucose clamp study 23 nonsmoking subjects with type 1 diabetes received a dose of 0.19 units/kg inhaled human insulin followed in random order by either 1) no exercise (NOEX group) or 30 min exercise starting, 2) 30 min after dosing (EX30), 3) 120 min after dosing (EX120), or 4) 240 min after dosing (EX240).RESULTS -Exercise changed the shape of the free plasma insulin curves, but compared with the NOEX group the area under the curve for free plasma insulin (AUC ins ) for the first 2 h after the start of exercise was unchanged for EX30 and EX240, while it was 15% decreased for EX120 (P Ͻ 0.01). The overall insulin absorption during 6 and 10 h after dosing was 13% decreased for EX30 (P Ͻ 0.005), 11% decreased for EX120 (P Ͻ 0.01), and unchanged for EX240. Exercise did not influence the maximum insulin concentration (C max ), while the time to C max was 22 min earlier for EX30 (P ϭ 0.04). The AUC for the glucose infusion rate (AUC GIR ) for 2 h after the start of exercise increased by 58% for EX30, 45% for EX120, and 71% for EX240 (all P Ͻ 0.02) compared with the NOEX group.CONCLUSIONS -Thirty minutes of moderate exercise led to unchanged or decreased absorption of inhaled insulin via AERx iDMS and faster C max for early exercise. Thus, patients using AERx iDMS can adjust insulin dose as usual independent of time of exercise, but they should be aware of the faster effect if exercising early after dosing.

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Pulmonary Insulin Administration Using the AERx® System: Physiological and Physicochemical Factors Influencing Insulin Effectiveness in Healthy Fasting Subjects

Cited by 70 publications

References 20 publications

Dose-Response Relationships of Inhaled Insulin Delivered via the Aerodose Insulin Inhaler and Subcutaneously Injected Insulin in Patients With Type 2 Diabetes

Dose-Response Relationships of Inhaled Insulin Delivered via the Aerodose Insulin Inhaler and Subcutaneously Injected Insulin in Patients With Type 2 Diabetes

Intensive Therapy With Inhaled Insulin via the AERx Insulin Diabetes Management System

The Effect of Exercise on the Absorption of Inhaled Human Insulin via the AERx Insulin Diabetes Management System in People With Type 1 Diabetes

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