Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Castle, Jessica R.; Youssef, Joseph El; Branigan, Deborah; Newswanger, Brett; Strange, Poul; Cummins, Martin J.; Shi, Leon; Prestrelski, Steven J.

doi:10.1177/1932296816653141

Cited by 33 publications

(21 citation statements)

References 17 publications

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“…times basal insulin levels, IOB from 0 to 2 U and IOB/TDD from 0 to 5%. The lowest glucagon dose to optimally treat mild hypoglycaemia was 125 lg when actual insulin levels were equal to baseline levels, which is in accordance with findings from previous studies [25,26]. In contrast, at very high insulin levels (se/ba-insulin > 3, IOB ≥ 3 U, IOB/ TDD > 8%), the optimum glucagon doses exceeded the amount (1000 lg) normally used for treating severe hypoglycaemia.…”

Section: Discussionsupporting

confidence: 89%

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Ranjan

Wendt

Schmidt

et al. 2017

Basic Clin Pharma Tox

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Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin-dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose-insulin-glucagon model was used to describe seven virtual patients with insulin pump-treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba-insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre-defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125-μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba-insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model-based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin-dependent glucagon dosing regimen for treatment of insulin-induced mild hypoglycaemia in patients with type 1 diabetes.

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Section: Discussionsupporting

confidence: 89%

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Ranjan

Wendt

Schmidt

et al. 2017

Basic Clin Pharma Tox

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“…Currently available glucagon formulations start degrading and form fibrils shortly after reconstitution, meaning that glucagon has to be replaced every day to avoid a loss in glucagon efficacy or pump occlusions attributable to fibrils . This has led to the search for stable liquid glucagon formulations not requiring reconstitution . Until now, “in‐use” drug stability and compatibility in an infusion‐pump (G‐Pump) has been shown for dimethylsulfoxid (DMSO) glucagon, which demonstrated sufficient efficacy at all three doses tested (0.3, 1.2 and 2.0 μg/kg) compared with GlucaGen; however, DMSO glucagon was associated with significantly more erythema and pain at the infusion site compared with GlucaGen.…”

Section: Discussionmentioning

confidence: 99%

“…Until now, “in‐use” drug stability and compatibility in an infusion‐pump (G‐Pump) has been shown for dimethylsulfoxid (DMSO) glucagon, which demonstrated sufficient efficacy at all three doses tested (0.3, 1.2 and 2.0 μg/kg) compared with GlucaGen; however, DMSO glucagon was associated with significantly more erythema and pain at the infusion site compared with GlucaGen. The majority of reactions were mild or moderate, but may limit the clinical utility of DMSO glucagon . Furthermore, initial preclinical reports indicate that the BioChaperone technology allows the formulation of stable ready‐to‐use liquid formulations of human glucagon suited for rescue therapy of severe hypoglycaemia .…”

Section: Discussionmentioning

confidence: 99%

Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus

Hövelmann

Olsen

Mouritzen

et al. 2018

Diabetes Obesity Metabolism

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Aim To characterize the pharmacokinetic and pharmacodynamic properties of dasiglucagon, a novel, stable and liquid formulated glucagon analogue, during hypoglycaemic and euglycaemic conditions in adult patients with type 1 diabetes mellitus. Research Design and Methods In this randomized double‐blind trial, 17 patients received four single subcutaneous doses (0.03, 0.08, 0.2 and 0.6 mg) of dasiglucagon (4 mg/mL formulation) under euglycaemic (plasma glucose [PG] 5.6 mmol/L [100 mg/dL]) or hypoglycaemic (PG 3.1‐3.7 mmol/L [56‐66 mg/dL]) conditions. For comparison, three doses (0.03, 0.08 and 0.2 mg) of a commercial glucagon formulation (Eli Lilly) were investigated at euglycaemia. Results Dasiglucagon led to a dose‐dependent and rapid increase in PG levels across all doses tested (mean increases 30 minutes post‐dosing of 2.2 to 4.4 mmol/L [39‐80 mg/dL] from euglycaemia and 1.3 to 5.2 mmol/L [24‐94 mg/dL] from hypoglycaemia), which was higher than the rises elicited by similar doses of commercial glucagon (1.7‐3.9 mmol/L [30‐71 mg/dL]). The median time (range) to an increase in PG of >1.1 mmol/L (20 mg/dL) was <20 (18‐19.5) minutes with 0.03 mg dasiglucagon and, with higher doses, the median times ranged from 9 to 15 minutes (commercial glucagon 13‐14 minutes). In hypoglycaemia, 0.03 and 0.08 mg dasiglucagon re‐established normoglycaemia (PG ≥3.9 mmol/L [70 mg/dL]) within median times of 14 and 10 minutes, respectively. Nausea and vomiting occurred more frequently with dasiglucagon than with commercial glucagon at identical doses which might be attributable to dasiglucagon's higher potency. Conclusion Dasiglucagon rapidly increased PG at doses of 0.03 to 0.6 mg in a dose‐dependent manner and, therefore, is a good candidate for use in dual‐hormone artificial pancreas systems.

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“…The advent of faster insulins [30] and availability of stable glucagon [31] may enhance the performance of single-hormone and bi-hormonal closed-loop systems, respectively. Although it is expected that no significant added expenses apart from those related to continuous glucose monitoring may be conferred on the user, longer studies evaluating long-term biomedical and psychosocial outcomes, as well as cost-effectiveness, are needed to justify and provide wider reimbursements for all users.…”

Section: Discussionmentioning

confidence: 99%

Closed-loop for type 1 diabetes – an introduction and appraisal for the generalist

Bally

Thabit

Hovorka

2017

BMC Med

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BackgroundRapid progress over the past decade has been made with the development of the ‘Artificial Pancreas’, also known as the closed-loop system, which emulates the feedback glucose-responsive functionality of the pancreatic beta cell. The recent FDA approval of the first hybrid closed-loop system makes the Artificial Pancreas a realistic therapeutic option for people with type 1 diabetes. In anticipation of its advent into clinical care, we provide a primer and appraisal of this novel therapeutic approach in type 1 diabetes for healthcare professionals and non-specialists in the field.DiscussionRandomised clinical studies in outpatient and home settings have shown improved glycaemic outcomes, reduced risk of hypoglycaemia and positive user attitudes. User input and interaction with existing closed-loop systems, however, are still required. Therefore, management of user expectations, as well as training and support by healthcare providers are key to ensure optimal uptake, satisfaction and acceptance of the technology. An overview of closed-loop technology and its clinical implications are discussed, complemented by our extensive hands-on experience with closed-loop system use during free daily living.ConclusionsThe introduction of the artificial pancreas into clinical practice represents a milestone towards the goal of improving the care of people with type 1 diabetes. There remains a need to understand the impact of user interaction with the technology, and its implication on current diabetes management and care.

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Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects

Cited by 33 publications

References 17 publications

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus

Closed-loop for type 1 diabetes – an introduction and appraisal for the generalist

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