Eli Lilly Japan K.K., 5-1-28 Isogamidori, Chuo-Ku, Kobe, 651-0086, Japan.
Eli Lilly and Company, Indianapolis, IN, USA.
Paediatr Drugs. 2023 May;25(3):377-387. doi: 10.1007/s40272-023-00565-y. Epub 2023 Mar 27.
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.
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.
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.
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.
This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.
在日本，鼻用胰高血糖素（NG）3 毫克被批准用于治疗糖尿病患儿的低血糖，但由于实际和伦理问题，尚未在日本儿童中进行 NG 临床研究。
本研究旨在通过建模和模拟为日本糖尿病儿科患者使用 NG3 毫克提供剂量合理性依据。
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至日本儿科患者。使用来自 7 项临床研究的数据进行群体药代动力学/药效学建模，其中包括 5 项非日本成年人研究、1 项日本成年人研究和 1 项非日本儿科患者研究。然后，使用模拟来估计 NG3 毫克给药后 3 个年龄组的日本儿科患者的胰高血糖素暴露和血糖反应：4 至<8 岁、8 至<12 岁和 12 至<18 岁。治疗成功定义为 NG3 毫克给药后 30 分钟内血糖从最低点升高至≥70 或≥20mg/dL。使用 NG 临床试验数据和静脉内和肌肉内胰高血糖素的已发表数据评估安全性与 NG3 毫克的预测最大胰高血糖素浓度的关系。
数据显示，NG3 毫克在日本和非日本成年人和非日本儿科患者中迅速且强烈地引起血糖反应，在不同研究中观察到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 3 个年龄组的低血糖日本儿科患者中，超过 99%将达到治疗成功。预测的 NG3 毫克对日本儿科患者的血糖反应与肌肉内胰高血糖素相当。在 NG 临床试验中，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，尽管日本儿科患者的预测最大浓度高于 NG 临床试验中的观察到的最大浓度，但与静脉内 1 毫克胰高血糖素的观察到的最大浓度相比，没有严重的安全问题，且显著更低。
本分析表明，在日本糖尿病儿科患者中，NG3 毫克具有强大的疗效且无严重的安全问题。
