Mona Darwish, Julie Passarell, Kelly Maxwell, James M. Youakim, Heather Bradley, Kathie M. Bishop
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引用次数: 0
摘要
美国批准口服体重带状给药方案的特非尼肽用于治疗年龄≥2岁的Rett综合征（RTT）患者。此次批准主要基于3期LAVENDER研究在5-20岁RTT女孩和女性中的有效性和安全性结果，并在DAFFODIL研究的支持数据下扩展到2-4岁的幼儿。根据早期临床人群药代动力学（popPK）模型和不同情景模拟选择体重带给药方案。我们报告了一个更新的popPK模型的开发和应用，以确认在LAVENDER研究中个体患者的稳态特非尼肽暴露在目标暴露范围内。方法：先前开发的基于9项临床研究数据的popPK模型基于包括LAVENDER研究在内的13项健康志愿者、儿童和成人患者的trofinetide临床研究进行了更新。使用PopPK模型和经验个体贝叶斯药代动力学参数估计来产生trofinetide暴露。使用来自LAVENDER研究受试者（n = 92）的药代动力学数据集的协变量数据来估计个体的稳态trofinetide暴露（0-12 h的浓度-时间曲线下面积[AUC0-12]）。在LAVENDER研究中，个体患者的稳态暴露被用来证实给药方案导致暴露在目标范围内。结果：在接受LAVENDER BID给药方案的5- 20岁儿童中[trofinetide 6 g （12 - 20 kg）、8 g （20-35 kg）、10 g （35-50 kg）和12 g (50 kg)]，模拟AUC0-12值与目标暴露范围重叠；中位AUC0-12值在所有体重波段的目标暴露范围内。结论：基于PopPK模型的模拟证实，在患有RTT的5-20岁女孩和妇女中，薰衣草中使用的体重带状特罗菲肽剂量达到了目标暴露。本文提供图形摘要。
Population Pharmacokinetic Modeling to Support Trofinetide Dosing for the Treatment of Rett Syndrome
Introduction
Oral trofinetide administered using a body weight-banded dosing regimen was approved in the US for the treatment of Rett syndrome (RTT) in patients aged ≥ 2 years. This approval was principally based on efficacy and safety findings of the phase 3 LAVENDER study in girls and women aged 5–20 years with RTT and extended to younger children aged 2–4 years with supporting data from the DAFFODIL study. Weight-banded dosing regimens were selected based on early clinical population pharmacokinetic (popPK) modeling and different scenario simulations. We report the development and application of an updated popPK model to confirm that steady-state trofinetide exposures achieved in individual patients in the LAVENDER study were within target exposure range.
Methods
A previously developed popPK model using data from nine clinical studies was updated based on 13 clinical studies of trofinetide in healthy volunteers and pediatric and adult patients, including the LAVENDER study. PopPK model and empiric individual Bayesian pharmacokinetic parameter estimates were used to generate trofinetide exposures. Covariate data from the pharmacokinetic dataset from LAVENDER study subjects (n = 92) were used to estimate individual steady-state trofinetide exposure (area under concentration–time curve over 0–12 h [AUC0–12]). Steady-state exposures in individual patients in the LAVENDER study were used to confirm that the dosing regimens resulted in exposures within the target range.
Results
Among 5- to 20-year-olds receiving the LAVENDER BID dosing regimen [trofinetide 6 g (12‒20 kg), 8 g (> 20‒35 kg), 10 g (> 35‒50 kg), and 12 g (> 50 kg)], simulated AUC0-12 values overlapped with the target exposure range; median AUC0–12 values were within target exposure range for all weight bands.
Conclusions
PopPK model-based simulations confirm that weight-banded trofinetide dosing used in LAVENDER in girls and women aged 5–20 years with RTT achieved target exposure.
期刊介绍：
Advances in Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all therapeutic areas. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged.
The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Advances in Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research.
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