Background

Nasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns.

Objective

The aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation.

Methods

We used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to < 8, 8 to < 12, and 12 to < 18 years. Treatment success was defined as an increase in blood glucose to ≥ 70 or ≥ 20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon.

Results

The data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that > 99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues.

Conclusions

This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.

中文翻译：

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使用药代动力学/药效动力学建模和仿真分析日本糖尿病儿科患者鼻胰高血糖素的剂量基本原理

背景

日本批准鼻胰高血糖素 (NG) 3 mg 用于治疗小儿糖尿病患者的低血糖症，但出于实际和伦理方面的考虑，尚未在日本儿童中进行鼻胰高血糖素临床研究。

客观的

本研究的目的是使用建模和模拟支持日本糖尿病儿科患者服用 NG 3 mg 的剂量原理。

方法

我们使用药代动力学/药效学桥接方法将可用的临床数据外推到日本儿科患者。使用七项临床研究的数据进行群体药代动力学/药效学建模，包括五项针对非日本成人的研究、一项针对日本成人的研究和一项针对非日本儿童患者的研究。然后使用模拟来估计 NG 3 mg 给药后的胰高血糖素暴露和葡萄糖反应，适用于三个年龄组的日本儿科患者：4 至 < 8 岁、8 至 < 12 岁和 12 至 < 18 岁。治疗成功定义为在给予 NG 3 mg 后 30 分钟内血糖从最低点增加至 ≥ 70 或 ≥ 20 mg/dL。

结果

数据显示，在日本和非日本成人以及非日本儿童患者中服用 3 毫克 NG 后，葡萄糖反应迅速而强烈，在不同研究中观察到的胰高血糖素暴露存在一些差异。药代动力学/药效学模型很好地描述了观察到的临床数据，模拟表明所有三个年龄组中 > 99% 的低血糖日本儿科患者将获得治疗成功。日本儿科患者对 NG 3 mg 的预测葡萄糖反应与肌肉注射胰高血糖素的反应相当。在 NG 临床研究中，最大浓度与常见不良事件（恶心、呕吐和头痛）的发生和严重程度无关。此外，日本儿科患者的预测最大浓度，

结论

该分析表明 NG 3 mg 在日本糖尿病儿科患者中具有强大的疗效，且没有严重的安全问题。