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A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

ABSTRACT: Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to capture the full effect and higher doses were not tested. Thus, a pharmacokinetic-GIR model was developed to simulate GIR for a sufficient time window of 20 h and for higher doses. A dose-response model was then generated from the simulated GIR profiles. The resulting model provides an ED50 for TI that is 5-fold higher than for RHI, a ratio that can be used as conversion factor for equivalent doses of RHI and TI.

SUBMITTER: Ruppel D

PROVIDER: S-EPMC5488128 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

Rüppel D D Dahmen R R Boss A A Jäger R R Grant M M Baughman R R Klabunde T T

CPT: pharmacometrics & systems pharmacology 20170601 6

Technosphere insulin (TI), an inhaled insulin with a fast onset of action, provides a novel option for the control of prandial glucose. A euglycemic glucose clamp study was performed to compare the effects of TI and regular human insulin (RHI) on the induced glucose infusion rate (GIR) in healthy volunteers. Generation of a dose-response relationship between insulin dose and effect (expressed as AUC of GIR) was not possible from the clinical data directly. The GIR recording time was too short to ...[more]

PMID: 28568813

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Project description:BACKGROUND:The majority of therapies have generally targeted fasting glucose control, and current mealtime insulin therapies have longer time action profiles than that of endogenously secreted insulin. The primary purpose of this study was to assess both glucose time-in-range (TIR: 70-180?mg/dL) and postprandial glucose excursions (PPGE) in 1-4?h using a real-time continuous glucose monitor (CGM) with Technosphere insulin (TI) versus insulin aspart in patients with type 1 diabetes (T1DM) on multiple daily injections (MDI). RESEARCH DESIGN AND METHODS:This pilot, investigator-led, collaborative, open-label, multicenter, clinical research trial enrolled 60 patients with T1DM with HbA1c levels ?6.5% and ?10%. Individuals were randomized to treatment with titrated TI (n?=?26) or titrated insulin aspart (n?=?34), stratified by baseline HbA1c levels (?8% or >8%). All were required to wear a real-time CGM throughout the trial. All patients in the TI group were advised to take supplemental inhalations at 1 and 2?h after meals if indicated based on postprandial glucose (PPG) values. The coprimary outcomes were assessed both in the full intent-to-treat population and in those individuals randomized to TI who were compliant with supplemental doses ?90% of the time (n?=?15). The CGM data were analyzed using linear regression models. RESULTS:Overall, those treated with TI versus aspart achieved comparable TIR, but less time spent in hypoglycemia (<60 and <50?mg/dL, both P?<?0.05). In the TI-compliant group (n?=?15), TIR was significantly greater (62.5%?±?2.6% vs. 53.8%?±?1.7%, P?=?0.009) and time in hyperglycemia >180?mg/dL was lower (34.2%?±?2.7% vs. 41.0%?±?1.7%, P?=?0.045) as compared with the aspart group. PPG was also significantly lower in the TI cohort at 60 and 90?min postmeal, and PPGE were lower in the TI-compliant group as compared with the aspart group over 1-4-h postmeal (P?<?0.05). In addition, there was weight gain in the aspart group compared with weight loss in the TI group (P?=?0.006) despite higher prandial TI insulin dose. CONCLUSIONS:We conclude that using TI appropriately at mealtimes with supplemental dosing improves prandial glucose (TIR and 1-4?h) control without any increase in time in hypoglycemia or weight gain in patients with T1DM on MDI. The study results support a larger study using a treat-to-target design to confirm these findings. Clinical trial reg. no. NCT03143816, clinicaltrials.gov .

Dataset Information

A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

Publications

A Population Dose-Response Model for Inhaled Technosphere Insulin Administered to Healthy Subjects.

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