Mizuno Tomoyuki, Fukuda Tsuyoshi, Emoto Chie, Mobberley-Schuman Paula S, Hammill Adrienne M, Adams Denise M, Vinks Alexander A
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Pediatr Blood Cancer. 2017 Aug;64(8). doi: 10.1002/pbc.26470. Epub 2017 Feb 16.
Sirolimus has recently been shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. Nevertheless, dosing information remains very limited especially for neonates and infants. The purpose of this study was to develop an age-appropriate sirolimus starting dosing regimen based on the developmental changes in drug elimination capacity using data collected in neonates and infants.
A recently developed sirolimus maturation model [Emoto et al. CPT Pharmacometrics Syst Pharmacol, 2016] was used to simulate clearance estimates using realistic age and weight covariates for age cohorts aged 0-24 months. Next, predose concentrations at steady state were generated for each age cohort of neonates and infants. Dose requirements to attain predefined target trough concentration ranges (10-15 and 5-10 ng/ml) were simulated across the different age groups. Starting doses were chosen to maximize the likelihood of achieving sirolimus-targeted concentrations.
The trajectory of simulated sirolimus clearances increased with age and was in agreement with the previous findings in the Phase 2 study. The proposed dosing regimens covered eight age cohorts and resulted in target attainment of more than 75-95% across selected regimens.
This study identified age-appropriate sirolimus dosing regimens for neonates and infants. The algorithm in combination with therapeutic drug management will facilitate sirolimus precision dosing in young children with vascular anomalies. A prospective evaluation is being planned.
西罗莫司最近已被证明对患有复杂血管异常的儿科患者有效且耐受性良好。然而，给药信息仍然非常有限，尤其是对于新生儿和婴儿。本研究的目的是利用在新生儿和婴儿中收集的数据，根据药物消除能力的发育变化，制定适合年龄的西罗莫司起始给药方案。
使用最近开发的西罗莫司成熟模型[Emoto等人，《临床药理学与系统药理学》，2016年]，通过0至24个月龄队列的实际年龄和体重协变量模拟清除率估计值。接下来，为新生儿和婴儿的每个年龄队列生成稳态下的给药前浓度。模拟了不同年龄组达到预定义目标谷浓度范围（10 - 15和5 - 10 ng/ml）所需的剂量。选择起始剂量以最大化达到西罗莫司目标浓度的可能性。
模拟的西罗莫司清除率轨迹随年龄增加，与2期研究中的先前发现一致。建议的给药方案涵盖了八个年龄队列，在选定的方案中，目标达成率超过75% - 95%。
本研究确定了适合新生儿和婴儿的西罗莫司给药方案。该算法与治疗药物管理相结合，将有助于对患有血管异常的幼儿进行西罗莫司精准给药。正在计划进行前瞻性评估。
