Dose-Response Relationships of Inhaled Insulin Delivered via the Aerodose Insulin Inhaler and Subcutaneously Injected Insulin in Patients With Type 2 Diabetes
- Dennis Kim, MD12,
- Sunder Mudaliar, MD12,
- Sithipol Chinnapongse, MD1,
- Neelima Chu, MD1,
- Sarah M. Boies, BS1,
- Trent Davis, BS1,
- Ayesh D. Perera, PHD3,
- Robert S. Fishman, MD3,
- David A. Shapiro, MD3 and
- Robert Henry, MD12
- 1Veterans Affairs San Diego Healthcare System, San Diego, California
- 2University of California-San Diego, San Diego, California
- 3Aerogen, Inc., Mountain View, California
- Address correspondence and reprint requests to Robert Henry, MD, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr. (111G), San Diego, CA 92161. E-mail: rrhenry{at}vapop.ucsd.edu
Abstract
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 (Tmax 77 ± 66 vs. 193 ± 104 min, P < 0.001) and time-to-peak metabolic effects (TGIRmax 240 ± 94 vs. 353 ± 60 min, P < 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 = 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.
Footnotes
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D.K. is an employee of and holds stock in Amylin Pharmaceuticals.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted June 23, 2003.
- Received February 7, 2003.
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