An open-label, multiple ascending dose trial of orally administered insulin Tregopil in patients with type 1 diabetes mellitus to evaluate its pharmacokinetics, pharmacodynamics, safety and tolerability

IF 5.4 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes, Obesity & Metabolism Pub Date : 2025-04-10 DOI:10.1111/dom.16327

Esther Latres PhD, Leona Plum-Moerschel MD, Sundara Moorthi Nainar Murugesan MPharm, Olivia Lou PhD, Jayanti Panda PhD, Ashwani Marwah MSc, R. Samsonraj MSc, C. L. Gopu MPharm, Subramanian Loganathan MD, Sandeep Nilkanth Athalye MD

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Abstract

Aim

This trial evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of oral insulin Tregopil (Part 1; results discussed in this paper) and the post-prandial glucose control with different meal types in comparison with insulin aspart (Part 2) in patients with type 1 diabetes mellitus (T1DM).

Materials and Methods

This Phase 1, open-label, multiple ascending dose (30/45/60 mg/60 + 30 mg rescue insulin Tregopil) trial enrolled 37 patients with T1DM (3 female [8.1%], 34 male [91.9%]; median age: 39.5 years). Following screening, patients entered a run-in phase to optimize their basal-bolus (insulin glargine and insulin aspart) insulin therapy, and insulin Tregopil was administered orally 10 min before the three major meals of the day in all cohorts during this period. Safety assessments included adverse events and hypo−/hyperglycaemic episodes, vital signs, electrocardiograms, laboratory safety parameters and physical examination. PK and PD were the secondary objectives.

Results

The overall safety profile of insulin Tregopil indicated no safety concerns except a PD effect (hypoglycaemia). The incidence of hypoglycaemia did not increase with increasing doses of insulin Tregopil, and none of the episodes were severe. In general, the variability of the PK/PD parameters was high. Insulin Tregopil demonstrated a rapid onset of action, with peak blood concentrations reached within 15–20 min post-dosing. Subsequently, insulin Tregopil exerted a PD effect for up to 105 min.

Conclusion

Fixed-dose insulin Tregopil reduced the requirement for insulin aspart supplementation, although it was not a viable stand-alone option for the daily management of T1DM. Insulin Tregopil could be explored with a flexible dosing approach and be titrated based on individual needs.

Trial Registration

The trial is registered at Clinicaltrials.gov (CT.gov identifier: NCT04141423). The ethical approval number for the protocol is 2019146.

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1型糖尿病患者口服Tregopil胰岛素的开放标签、多次递增剂量试验，以评估其药代动力学、药效学、安全性和耐受性

目的评价口服Tregopil胰岛素的安全性、耐受性、药代动力学（PK）和药效学（PD）。1型糖尿病（T1DM）患者餐后血糖控制与不同餐型与天冬氨酸胰岛素（Part 2）的比较材料与方法该ⅰ期开放标签、多次递增剂量（30/45/60 mg/60 + 30 mg援救胰岛素Tregopil）试验纳入37例T1DM患者(女性3例[8.1%]，男性34例[91.9%]；中位年龄：39.5岁)。筛选后，患者进入磨合期，以优化其基础剂量（甘精胰岛素和天冬氨酸胰岛素）胰岛素治疗，在此期间，所有队列均在一日三餐前10分钟口服Tregopil胰岛素。安全性评估包括不良事件和低血糖/高血糖发作、生命体征、心电图、实验室安全参数和体格检查。PK和PD是次要目标。结果Tregopil胰岛素的总体安全性分析显示，除了PD效应（低血糖）外，没有其他安全性问题。低血糖的发生率没有随着Tregopil胰岛素剂量的增加而增加，并且没有严重的发作。总的来说，PK/PD参数的变异性较大。Tregopil胰岛素起效迅速，给药后15-20分钟内血药浓度达到峰值。随后，Tregopil胰岛素发挥PD效应长达105分钟。结论：固定剂量Tregopil胰岛素降低了对间门冬氨酸胰岛素补充的需求，尽管它不是T1DM日常管理的可行选择。Tregopil胰岛素可以探索灵活的给药方法，并根据个人需要进行滴定。该试验在Clinicaltrials.gov （CT.gov标识符：NCT04141423）上注册。该方案的伦理批准号为2019146。

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来源期刊

Diabetes, Obesity & Metabolism 医学-内分泌学与代谢

CiteScore

10.90

自引率

6.90%

发文量

319

审稿时长

3-8 weeks

期刊介绍： Diabetes, Obesity and Metabolism is primarily a journal of clinical and experimental pharmacology and therapeutics covering the interrelated areas of diabetes, obesity and metabolism. The journal prioritises high-quality original research that reports on the effects of new or existing therapies, including dietary, exercise and lifestyle (non-pharmacological) interventions, in any aspect of metabolic and endocrine disease, either in humans or animal and cellular systems. ‘Metabolism’ may relate to lipids, bone and drug metabolism, or broader aspects of endocrine dysfunction. Preclinical pharmacology, pharmacokinetic studies, meta-analyses and those addressing drug safety and tolerability are also highly suitable for publication in this journal. Original research may be published as a main paper or as a research letter.