背景:西罗莫司越来越多地用于治疗与mTOR通路过度激活相关的疾病。尽管有潜力,缺乏关于其在所有年龄组的长期安全性的证据,特别是在儿科患者中,限制了它的进一步应用。本研究旨在评估西罗莫司的长期安全性,特别关注其对儿科患者生长模式的影响。
方法:这项汇总分析包括两项为期10年的前瞻性队列研究,包括1,738名被诊断患有结节性硬化症和/或淋巴管肌瘤病的参与者(年龄5天至69岁)。所有参与者均未服用mTOR抑制剂,并接受1mg/m²/天的西罗莫司,在两周的滴定期内进行剂量调整,以维持谷值血液浓度在5至10ng/ml(最大剂量2mg)之间。身体生长指标,造血,肝脏,肾功能,和血脂水平均为主要结局,并进行分析.记录不良事件及相关管理。
结果:西罗莫司给药并未导致偏离正常生长范围,但是较高的剂量与身高超过2SD的Z评分呈正相关,体重,BMI。红细胞和白细胞计数的瞬时升高,伴随着高脂血症,主要在治疗的第一年内观察到。其他测量参数基本保持不变,仅显示与药物使用的弱相关性。口腔炎是最常见的不良事件(920/1738,52.9%)。在成年女性中,观察到月经紊乱占48.5%(112/217)。
结论:西罗莫司的长期给药对儿童的体格生长模式没有不良影响,也没有显著的造血改变,肝脏,肾功能,或脂质水平。对生长的潜在剂量依赖性影响值得进一步探索。
背景:儿科患者:中国临床试验注册,不。ChiCTR-OOB-15,006,535。成年患者:临床试验,不。NCT03193892。
BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.
METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.
RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).
CONCLUSIONS: Sirolimus\'s long-term administration is not associated with adverse effects on children\'s physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration.
BACKGROUND: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.