Improving Efficacy of Inhaled Technosphere Insulin (Afrezza) by Postmeal Dosing: In-silico Clinical Trial with the University of Virginia/Padova Type 1 Diabetes Simulator

Abstract

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.

Personalized blood glucose prediction: A hybrid approach using grammatical evolution and physiological models

“…The FDA-approved simulator used in this work is a valid substitute for the preclinical testing of novel technologies in diabetes care (see, e.g., [ 43 ][ 44 ][ 45 ]). However, the use of in silico data is not meant as substitute to human trial; rather, it can be considered a good starting point for evaluating our GE method: in fact simulated data are complete, i.e.…”

Possible Ways to Improve Postprandial Glucose Control in Type 1 Diabetes

“…80 A simulation study using modeled data from TI clinical trials suggested that higher doses of TI premeal or split dosing premeal and postmeal of TI may provide improved PPG profile with lesser fluctuations in postmeal glucose than conventional treatment with subcutaneously administered rapid-acting insulin products, and would be likely to do so without increasing the risk of hypoglycemia. 91 In current clinical use, there are higher rates of reported ''underdosing'' of TI as documented by lesser clinical effect when 1:1 mealtime insulin dose conversion is used. However, with additional clinical experience, patients and healthcare providers have been advised to consider the higher dose conversion when switching between RAIA and TI, and appropriate titration may allow for more aggressive and higher dosing of TI when clinically indicated.…”

In silico assessment of biomedical products: The conundrum of rare but not so rare events in two case studies

“…Designing a clinical trial to identify the optimal dosing regimen and the optimal titration rule would be prohibitively expensive because countless combinations would need to be tested. Thus, we performed in silico trials translating the known pharmacokinetic profile of TI (and insulin Lispro as comparator) into the expected post-prandial glucose response following a meal tolerance test 101 . The simulations suggested that post-meal dosing (at 15 or 30 min after start of the meal) and split dosing (with 15 or 30 min split times) results in a flatter post-prandial glucose profile than at-meal dosing (Figure 4).…”