Retlich Silke, Duval Vincent, Graefe-Mody Ulrike, Friedrich Christian, Patel Sanjay, Jaehde Ulrich, Staab Alexander
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany,
Clin Pharmacokinet. 2015 Jul;54(7):737-50. doi: 10.1007/s40262-014-0232-4.
Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM.
Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination.
The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC50) and the concentration leading to 80 % DPP-4 inhibition was <20 %.
These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.
利格列汀是一种二肽基肽酶（DPP）-4抑制剂，用于治疗2型糖尿病（T2DM）。进行了群体药代动力学和药效学分析，以表征临床相关的内在/外在因素（协变量）对T2DM患者利格列汀暴露量和DPP-4抑制作用的影响。
利格列汀血浆浓度和DPP-4活性数据来自四项研究（两项1期研究，两项2b期研究）。使用NONMEM软件实施非线性混合效应建模技术。所研究的协变量包括人口统计学信息和实验室值，如肝酶水平和肌酐清除率，以及与研究相关的因素，如二甲双胍联合治疗。使用逐步向前纳入/向后排除法研究协变量对描述药代动力学和药代动力学/药效学关系参数的影响。
药代动力学分析纳入了462例患者的6907次血浆利格列汀浓度测量值；药代动力学/药效学分析纳入了607例患者的9674次血浆DPP-4活性和利格列汀血浆浓度测量值。非线性药代动力学由一个目标介导的药物处置模型描述，该模型考虑了利格列汀与其靶点DPP-4的浓度依赖性结合。每个单一协变量的协变量分布第5和第95百分位数与中位数之间的暴露量差异<20%。同样，协变量对半数最大效应（EC50）和导致80%DPP-4抑制的浓度的影响<20%。
这些分析表明，所研究的因素在临床相关程度上不会改变利格列汀的药代动力学和DPP-4抑制活性，并且基于年龄、性别和体重等因素无需调整剂量。
