AIMS To investigate the impact on weight loss of the treatment changes in overweight or obese people that may be needed in case of gastrointestinal (GI) tolerability issues during escalation of the glucagon-like peptide-1 analogue liraglutide. MATERIALS AND METHODS The individual longitudinal body weight data from the main trial periods of three phase II/III trials in overweight or obese patients (56-week treatment with once-daily liraglutide 1.2, 1.8, 2.4 or 3.0 mg or placebo, n = 4952) were analysed using a non-linear mixed-effect modelling approach. Individual pharmacokinetic profiles were derived based on published pharmacokinetic models. Baseline body weight, baseline glycated haemoglobin (HbA1c), age, gender, diabetes status (no diabetes, prediabetes or type 2 diabetes), race and trial region were investigated as covariates. As a form of external validation, the model was used to predict the weight regain after treatment cessation at week 56 (data not included in model development). RESULTS A pharmacokinetic/pharmacodynamic model provided an adequate description of the weight loss trajectories for all studied doses. Gender and diabetes status were identified as the most influential covariates, and an underlying seasonal weight fluctuation was identified. Slower than that recommended, one-week dose-escalation algorithms led up to 2 weeks slower initial weight loss but similar long-term weight loss trajectories. CONCLUSIONS The relationship between liraglutide systemic exposure and weight loss was successfully established in overweight or obese people. The model could predict the time course of weight regain after treatment cessation and suggests that GI tolerability can be mitigated by slower escalation with only minor impact on the weight loss trajectory.

中文翻译：

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剂量递增方案和药物停用对利拉鲁肽3.0 mg减肥效果的影响：一种基于模型的方法。

目的研究在胰高血糖素样肽-1类似物利拉鲁肽逐步升级期间如果胃肠道（GI）耐受性问题可能需要的超重或肥胖人群治疗改变对体重减轻的影响。材料和方法来自超重或肥胖患者（三周II / III期试验的主要试验阶段的个人纵向体重数据（使用利拉鲁肽每天一次，1.2、1.8、2.4或3.0 mg或安慰剂治疗56周，n = 4952） ）使用非线性混合效应建模方法进行了分析。基于公开的药代动力学模型推导了各个药代动力学特征。将基线体重，基线糖化血红蛋白（HbA1c），年龄，性别，糖尿病状态（无糖尿病，前驱糖尿病或2型糖尿病），种族和试验区域作为协变量进行了研究。作为外部验证的一种形式，该模型用于预测第56周停药后的体重恢复（数据未包括在模型开发中）。结果药代动力学/药效学模型提供了所有研究剂量的减肥轨迹的充分描述。性别和糖尿病状态被确定为最有影响的协变量，并确定了潜在的季节性体重波动。比建议的速度慢，一周的剂量递增算法导致最初的体重减轻慢了2周，但长期体重减轻轨迹却差不多。结论利拉鲁肽全身暴露与体重减轻之间的关系已在超重或肥胖人群中成功建立。