Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Eur J Pharm Sci. 2017 Nov 15;109S:S124-S131. doi: 10.1016/j.ejps.2017.05.037. Epub 2017 May 17.
Sirolimus is the first drug to show efficacy in the treatment of patients with complicated vascular anomalies. The current study expands on the evolution of a PK model-based strategy for the precision dosing of sirolimus as part of prospective concentration controlled clinical trials in pediatric patients with vascular anomalies. Twelve month follow up data collected from 52 pediatric patients participating in the Phase 2 clinical trial were analyzed. Target attainment across the age range of 3weeks to 18years after 2-3months of therapy was 94% (49 out of 52 patients). The mean sirolimus dose to achieve the target of ~10ng/mL for patients older than 2years was 1.8mg/m twice daily (range 0.8-2.9), while it was 0.7 to 1.6mg/m twice daily for patients 3weeks of age to 2years. A total of 676 blood concentration data were used for the population PK analysis by nonlinear mixed effect modeling using NONMEM. The final model included a maturation function for sirolimus clearance and allometrically scaled body weight to account for size differences. The mean allometrically scaled sirolimus clearance estimates increased from 3.9 to 17.0L/h per 70kg with age from shortly after the birth to 2years of age while the mean estimate for patients older than 2years was 18.5L/h per 70kg. The developed model based dosing strategy provides a foundation for ongoing efforts to define the sirolimus exposure-response and clinical outcome relationships across the pediatric age spectrum from birth to adolescence.
西罗莫司是第一种在治疗复杂血管异常患者方面显示出疗效的药物。本研究扩展了基于 PK 模型的策略的演变，以实现精准用药，作为前瞻性浓度控制临床试验的一部分，该策略用于儿科血管异常患者。对 52 名参与 2 期临床试验的儿科患者进行了 12 个月的随访数据分析。在 2-3 个月的治疗后，3 周至 18 岁年龄范围内的目标达标率为 94%（52 例患者中有 49 例）。对于年龄大于 2 岁的患者，实现目标 ~10ng/mL 的平均西罗莫司剂量为每天两次 1.8mg/m（范围为 0.8-2.9），而对于 3 周至 2 岁的患者，剂量为每天两次 0.7 至 1.6mg/m。采用 NONMEM 通过非线性混合效应模型对总共 676 个血药浓度数据进行群体 PK 分析。最终模型包括西罗莫司清除率的成熟功能和按比例缩放的体重，以解释大小差异。按比例缩放的平均西罗莫司清除率估计值从出生后不久到 2 岁时从 3.9 增加到 17.0L/h/70kg，而大于 2 岁的患者的平均估计值为 18.5L/h/70kg。所开发的基于模型的给药策略为定义西罗莫司暴露-反应和临床结果关系提供了基础，该关系涵盖了从出生到青春期的儿科年龄范围。
