Fixed Dosing of Leuprolide Acetate, a GnRH Agonist, in Children with Central Precocious Puberty: A Population Pharmacokinetic Justification.

IF 3.3 3区医学 Q1 PEDIATRICS

Pediatric Drugs Pub Date : 2026-05-01 Epub Date: 2026-03-13 DOI:10.1007/s40272-025-00733-2

Chay Ngee Lim, Omar N Al Yacoub, Nael M Mostafa, Ahmed Hamed Salem

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引用次数: 0

Abstract

Background: Central precocious puberty is the early onset of puberty due to premature activation of the hypothalamic-pituitary-gonadal axis, which can reduce adult height. Leuprolide, a gonadotropin-releasing hormone agonist, reduces gonadotropin secretion and is the standard treatment for central precocious puberty.

Objective: This study aimed to build a population model to describe the pharmacokinetics of a 3-month leuprolide acetate depot formulation in pediatric patients with central precocious puberty, evaluate covariate effects (age and weight) on leuprolide pharmacokinetics, and assess flat-dosing feasibility in pediatrics.

Methods: Samples from 48 patients (aged 1-10 years) were collected over 24 weeks following the administration of 11.25 and 30 mg of a leuprolide acetate 3-month depot formulation. A population pharmacokinetic model was developed using non-linear mixed-effects modeling (NONMEM). Covariate effects were tested using a forward inclusion and backward elimination approach and exploratory data analysis.

Results: A one-compartment model with immediate and delayed first-order absorption and proportional error model best described leuprolide pharmacokinetics in children. A transit compartment model characterized the delayed absorption. Apparent clearance and volume estimates were 181 L/day and 7.11 L, respectively, which were in alignment with those estimated in adult patients with prostate cancer. The immediate and delayed absorption rate constants were 0.441 day^-1 and 0.00879 day^-1, respectively. The number of transit compartments and the mean transit time were 3 and 34.1 days, respectively. No covariates significantly affected leuprolide pharmacokinetics.

Conclusions: The developed model adequately characterized leuprolide pharmacokinetics in pediatrics. No significant covariate effects were observed, supporting the use of a fixed leuprolide dose in pediatrics.

Clinical trial registration: NCT00635817, registered 13 March, 2008.

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GnRH激动剂醋酸Leuprolide在中枢性性早熟儿童中的固定剂量：群体药代动力学证明。

背景：中枢性性早熟是由于下丘脑-垂体-性腺轴过早激活而导致的性早熟，可使成人身高降低。Leuprolide是一种促性腺激素释放激素激动剂，可减少促性腺激素的分泌，是中枢性性早熟的标准治疗方法。目的：建立人群模型，描述中枢性性性早熟儿童3个月期醋酸丙uprolide depot制剂的药代动力学，评估年龄和体重对丙uprolide药代动力学的共变量影响，并评估儿科平给药的可行性。方法：48例患者（年龄1 ~ 10岁）在给予11.25和30 mg醋酸leuprolide 3个月贮存制剂后24周内采集样本。采用非线性混合效应模型（NONMEM）建立种群药代动力学模型。使用前向纳入和后向排除方法和探索性数据分析来检验协变量效应。结果：一种具有即时和延迟一阶吸收的单室模型和比例误差模型最能描述丙烯醚在儿童体内的药代动力学。过境室模型表征了延迟吸收。表观清除率和体积估计分别为181 L/天和7.11 L，这与成年前列腺癌患者的估计一致。直接吸收速率常数为0.441 d -1，延迟吸收速率常数为0.00879 d -1。运输车厢数和平均运输时间分别为3天和34.1天。没有协变量显著影响良丙利酯的药代动力学。结论：所建立的模型充分表征了异丙脲在儿科的药代动力学。没有观察到显著的协变量效应，支持在儿科使用固定剂量的leuprolide。临床试验注册：NCT00635817，注册于2008年3月13日。

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来源期刊

Pediatric Drugs PEDIATRICS-PHARMACOLOGY & PHARMACY

CiteScore

7.20

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： Pediatric Drugs promotes the optimization and advancement of all aspects of pharmacotherapy for healthcare professionals interested in pediatric drug therapy (including vaccines). The program of review and original research articles provides healthcare decision makers with clinically applicable knowledge on issues relevant to drug therapy in all areas of neonatology and the care of children and adolescents. The Journal includes: -overviews of contentious or emerging issues. -comprehensive narrative reviews of topics relating to the effective and safe management of drug therapy through all stages of pediatric development. -practical reviews covering optimum drug management of specific clinical situations. -systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. -Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in the pediatric population. -original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Pediatric Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.