Johnston Curtis K, Eudy-Byrne Rena J, Elmokadem Ahmed, Nock Valerie, Marquard Jan, Soleymanlou Nima, Riggs Matthew M, Liesenfeld Karl-Heinz
Metrum Research Group, Tariffville, CT 06081, USA.
Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany.
Pharmaceutics. 2021 Apr 2;13(4):485. doi: 10.3390/pharmaceutics13040485.
In clinical trials, sodium-glucose co-transporter (SGLT) inhibitor use as adjunct to insulin therapy in type 1 diabetes (T1D) provides glucometabolic benefits while diabetic ketoacidosis risk is increased. The SGLT2 inhibitor empagliflozin was evaluated in two phase III trials: EASE-2 and EASE-3. A low, 2.5-mg dose was included in EASE-3 only. As the efficacy of higher empagliflozin doses (i.e., 10 and 25 mg) in T1D has been established in EASE-2 and EASE-3, a modeling and simulation approach was used to generate additional supportive evidence on efficacy for the 2.5-mg dose. We present the methodology behind the development and validation of two modeling and simulation frameworks: M-EASE-1, a semi-mechanistic model integrating information on insulin, glucose, and glycated hemoglobin; and M-EASE-2, a descriptive model informed by prior information. Both models were developed independently of data from EASE-3. Simulations based on these models assessed efficacy in untested clinical trial scenarios. In this manner, the models provide supportive evidence for efficacy of low-dose empagliflozin 2.5 mg in patients with T1D, illustrating how pharmacometric analyses can support efficacy assessments in the context of limited data.
在临床试验中，1型糖尿病（T1D）患者使用钠-葡萄糖协同转运蛋白（SGLT）抑制剂作为胰岛素治疗的辅助手段，虽能带来糖代谢益处，但会增加糖尿病酮症酸中毒风险。在两项III期试验（EASE-2和EASE-3）中对SGLT2抑制剂恩格列净进行了评估。仅在EASE-3中纳入了2.5毫克的低剂量。鉴于在EASE-2和EASE-3中已证实恩格列净较高剂量（即10毫克和25毫克）对T1D的疗效，采用建模与模拟方法来生成关于2.5毫克剂量疗效的更多支持性证据。我们介绍两个建模与模拟框架的开发和验证背后的方法：M-EASE-1，一个整合胰岛素、葡萄糖和糖化血红蛋白信息的半机制模型；以及M-EASE-2，一个基于先前信息的描述性模型。这两个模型均独立于EASE-3的数据开发。基于这些模型的模拟评估了未经测试的临床试验场景中的疗效。通过这种方式，这些模型为低剂量2.5毫克恩格列净对T1D患者的疗效提供了支持性证据，说明了在数据有限的情况下，药代动力学分析如何支持疗效评估。
