Chigutsa Emmanuel, Her Lucy, Ma Xiaosu, Urva Shweta, Schneck Karen
Eli Lilly and Company, Indianapolis, Indiana, USA.
Clin Pharmacol Ther. 2025 Jun 25. doi: 10.1002/cpt.3750.
About half of the world's population is living with overweight or obesity. Tirzepatide is an approved treatment for chronic weight management. We sought to characterize the exposure-response relationship for weight reduction in patients with overweight or obesity and quantify the associated changes in body composition. Monthly body weight measurements were available from 2,539 study participants in a phase 3 clinical trial investigating placebo, 5, 10, or 15 mg of tirzepatide administered once-weekly. The dependent variables used for modeling were fat-free mass (FFM) and fat mass. These FFM and fat mass values were calculated for each patient based on their total body weight, height, and sex. The exposure-response model revealed that administration of tirzepatide resulted in three times greater reduction of fat mass than that of FFM. This differential effect resulted in improved body composition over time. The model results showed good agreement with available data from a subset (10%) of clinical trial participants who had dual energy x-ray absorptiometry (DXA) measurements. For the same drug exposure, females achieved greater weight reduction than males. Study participants with higher baseline weight or body mass index at baseline had a slower rate of weight reduction and were expected to take longer to reach their nadir weight. We present and propose the use of a pharmacometric-based body composition model to describe weight reduction in future clinical trials investigating similar drugs in similar patient populations, in lieu of DXA scans. In such future trials, our approach can be used to describe exposure-response relationships, optimize doses, and investigate covariates, while considering potential differences in fat mass and FFM.
世界上约一半的人口超重或肥胖。替尔泊肽是一种已获批准用于慢性体重管理的治疗药物。我们试图描述超重或肥胖患者体重减轻的暴露-反应关系，并量化身体成分的相关变化。在一项3期临床试验中，有2539名研究参与者提供了每月体重测量数据，该试验研究了安慰剂、每周一次给药5、10或15毫克替尔泊肽的情况。用于建模的因变量是去脂体重（FFM）和脂肪量。这些FFM和脂肪量值是根据每位患者的总体重、身高和性别计算得出的。暴露-反应模型显示，替尔泊肽给药导致的脂肪量减少幅度是FFM的三倍。随着时间的推移，这种差异效应导致身体成分得到改善。模型结果与临床试验参与者子集（10%）中进行双能X线吸收法（DXA）测量的可用数据显示出良好的一致性。对于相同的药物暴露，女性的体重减轻幅度大于男性。基线体重或基线体重指数较高的研究参与者体重减轻速度较慢，预计达到最低体重所需的时间更长。我们提出并建议使用基于药代动力学的身体成分模型来描述未来在类似患者群体中研究类似药物的临床试验中的体重减轻情况，以替代DXA扫描。在未来的此类试验中，我们的方法可用于描述暴露-反应关系、优化剂量和研究协变量，同时考虑脂肪量和FFM的潜在差异。
