Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Clin Pharmacokinet. 2020 Jan;59(1):81-96. doi: 10.1007/s40262-019-00798-6.
The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age.
Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies.
The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 μg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects.
Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed.
This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).
此前已在成人中证实了两种去氨加压素（dDAVP）制剂的生物等效性，dDAVP 是一种血管加压素类似物，用于治疗儿童夜间遗尿症。但尚未在儿童中进行研究。本研究旨在研究这两种制剂在禁食和进食的儿童（包括 6 岁以下的患者）中的药代动力学（PK）和药效学（PD）。
将先前发表的一篇 PK 研究和一篇 PK/PD 研究的数据与一项新的 6 个月至 8 岁儿童的 PK/PD 研究相结合，并使用群体 PK/PD 建模进行分析。进行模拟以进一步探索两种制剂的相对生物利用度，并评估当前的给药方案。
采用双输入模型对冻干制剂的复杂吸收行为进行建模，该模型与一个具有线性消除的一室模型和一个将 dDAVP 浓度与产生的尿量和渗透压联系起来的间接反应模型相关联。最终模型很好地描述了观察到的数据，并阐明了两种制剂的生物等效性和治疗等效性的复杂性。模拟表明，目前使用冻干制剂 120μg 固定剂量的给药方案并不适合儿童，因为在儿童服用 dDAVP 时假设他们处于进食状态。建议了一种新的基于年龄和体重的给药方案，并表明该方案可改善和更好地调整疗效。
同一种药物的两种制剂在成人中的生物等效性和治疗等效性数据不能轻易外推至儿童。本研究表明了进行良好设计的儿科临床试验的重要性，以及如何使用混合效应模型进行分析以得出临床相关结论。应进行后续临床试验以测试建议的 dDAVP 给药方案。
该试验已在 www.clinicaltrials.gov 上注册（标识符 NCT02584231；EudraCT 2014-005200-13）。
