Improving Efficacy of Inhaled Technosphere Insulin (Afrezza) by Postmeal Dosing: In-silico Clinical Trial with the University of Virginia/Padova Type 1 Diabetes Simulator
Open accessAbstract
BACKGROUND: Technosphere(®) insulin (TI), an inhaled human insulin with a fast onset of action, provides a novel option for the control of prandial glucose. We used the University of Virginia (UVA)/Padova simulator to explore in-silico the potential benefit of different dosing regimens on postprandial glucose (PPG) control to support the design of further clinical trials. Tested dosing regimens included at-meal or postmeal dosing, or dosing before and after a meal (split dosing). METHODS: Various dosing regimens of TI were compared among one another and to insulin lispro in 100 virtual type-1 patients. Individual doses were identified for each regimen following different titration rules. The resulting postprandial glucose profiles were analyzed to quantify efficacy and the risk for hypoglycemic events. RESULTS: This approach allowed us to assess the benefit/risk for each TI dosing regimen and to compare results with simulations of insulin lispro. We identified a new titration rule for TI that could significantly improve the efficacy of treatment with TI. CONCLUSION: In-silico clinical trials comparing the treatment effect of different dosing regimens with TI and of insulin lispro suggest that postmeal dosing or split dosing of TI, in combination with an appropriate titration rule, can achieve a superior postprandial glucose control while providing a lower risk for hypoglycemic events than conventional treatment with subcutaneously administered rapid-acting insulin products.
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The Hovorka model and the UVAPadova model were originally formulated to represent the physiological behaviour of T1DM individuals, and no modification is necessary for the purpose of the present work.
“On the contrary, the Hovorka model and the UVAPadova model were originally formulated to represent the physiological behaviour of T1DM individuals, and no modification is necessary for the purpose of the present work.”
From A comparison among three maximal mathematical models of the glucose-insulin system (2021) · cites this paper as [26]
The Introduction and Research Design and Methods (page numbers unavailable) identify the UVA/Padova simulator as a model of T1D physiology using virtual T1D subjects. The paper does not discuss the Hovorka model or establish that neither model needs modification for the citing authors’ work. Indeed, its Methods describe incorporating an inhaled-insulin pharmacokinetic module into the UVA/Padova simulator. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe Hovorka model and the UVAPadova Simulator describe only the glucose metabolism of a subject with type 1 diabetes.
“While the Hovorka model and the UVAPadova Simulator only describe the glucose metabolism of a subject with type 1 diabetes, the Sorensen model was formulated to simulate the behaviour of both normal and diabetic individuals.”
From A comparison among three maximal mathematical models of the glucose-insulin system (2021) · cites this paper as [26]
The Introduction and Research Design and Methods describe the UVA/Padova simulator as modeling virtual patients with type 1 diabetes. The Methods specify glucose–insulin–glucagon dynamics, rather than glucose alone. Our copy does not address the Hovorka model or the comparison with the Sorensen model (pages unavailable). (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe parameters of the Hovorka and UVA/Padova models are indicated for a diabetic individual.
“The parameters of the Hovorka and UVA/Padova models are instead indicated for a diabetic individual, but the more compact formulation of the Hovorka model requires fewer modifications to obtain a good fit.”
From A comparison among three maximal mathematical models of the glucose-insulin system (2021) · cites this paper as [26]
In Research Design and Methods (page unavailable), the paper says the UVA/Padova type 1 diabetes simulator assigns subject-specific parameters drawn to reflect variability in the type 1 diabetes population. It does not discuss the Hovorka model, so it supports the claim about UVA/Padova parameters but not the claim about Hovorka parameters. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe formulation adopted in the UVAPadova model is marginally more complicated: if the parameter ka1 is set to zero and the parameter ka2 is set to the same value as the parameter kd, then the two formulations are equivalent.
“The formulation adopted in the UVAPadova model is marginally more complicated: if the parameter ka1 is set to zero and the parameter ka2 is set to same value as the parameter kd, then the two formulations are equivalent.”
From A comparison among three maximal mathematical models of the glucose-insulin system (2021) · cites this paper as [26]
The Research Design and Methods section describes the UVA/Padova simulator’s insulin pharmacokinetic models, but does not compare the claimed formulations or state that setting ka1 to zero and ka2 equal to kd makes them equivalent. Searches for those parameters and for an equivalent-formulations comparison found no passage addressing the claim. Page numbers were not available in our copy. (LLM, conf=0.77)
Experimental — accuracy not yet measured
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- Authors
- Visentin, R., Giegerich, C., Jäger, R., Dahmen, R., Boss, A., Grant, M., Dalla Man, C., Cobelli, C., & Klabunde, T.
- Affiliations
- University of Padua (IT)
- Sanofi (Germany) (DE)
- Sanofi (United States) (US)
- MannKind Corporation (United States) (US)
- University of Padova
- Corresponding author
- Klabunde, Thomas
- Venue
- Diabetes Technology & Therapeutics
- Publisher
- SAGE Publications
- Published
- 2016-09
- Volume
- 18
- Issue
- 9
- Pages
- 574-585
- ISSN
- 1520-9156 (ISSN-L)
- 1557-8593
- PMC
- PMC5035370
- OpenAlex
- W2473968961
- Cited by
- 36
- References
- 18
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 1
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Technology & Therapeutics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
- Keywords
- inhaled insulin, Technosphere insulin, Afrezza, type 1 diabetes, postprandial glucose control, dosing regimen, split dosing, insulin lispro, hypoglycemia risk, in silico clinical trials, virtual patients, prandial insulin
- MeSH terms
- Administration, Inhalation, Computer Simulation, Diabetes Mellitus, Type 1, Drug Administration Schedule, Humans, Hypoglycemic Agents, Insulin, Postprandial Period
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