Z01: Non-Participant Specific Deviation in Pharmacokinetics and Safety Profile of Digoxin in Infants with Single-Ventricle Congenital Heart Disease

Non-Participant Specific Deviation (Site Deviations)
Study Description
This study was a prospective, multi-center, open-label, pharmacokinetic (PK) and safety profile study. The study was designed to gather population-specific PK data to identify the optimal dose in a population of infants with single-ventricle (SV) congenital heart disease (CHD) and to obtain the safety profile of digoxin in infants age ≤ 30 days of life at time of stage 1 palliation. PK analysis was primarily performed using population PK methodologies. Simulations suggested that to maximize the proportion of infants with SV CHD achieving a minimum concentration on steady state between 0.5 and 2 ng/mL, as recommended in the current digoxin package insert, doses should be optimized based on weight, estimated glomerular filtration rate, and postnatal age. Two fatal serious adverse events (both resulting from hypoplastic left heart syndrome) were reported, but they were not related to study drug. Based on these data, digoxin appears safe in infants with SV CHD. The study population (N=50) was comprised of infants with single-ventricle congenital heart disease status post-surgical or hybrid stage 1 palliation but prior to surgical stage 2 palliation.

非受试者特异性偏差（研究中心偏差）
研究概况
本研究为一项前瞻性、多中心、开放标签的药代动力学（pharmacokinetic，PK）与安全性评价研究，旨在收集人群特异性药代动力学数据，以明确单心室（single-ventricle，SV）先天性心脏病（congenital heart disease，CHD）患儿群体的最优给药剂量，并评估出生后≤30天、接受Ⅰ期姑息治疗的婴儿使用地高辛的安全性特征。本研究的药代动力学分析主要采用群体药代动力学方法开展。
模拟结果显示，为使符合当前地高辛药品说明书推荐要求的单心室先天性心脏病患儿稳态最低血药浓度达到0.5~2 ng/mL的比例最大化，应根据患儿体重、估算肾小球滤过率（estimated glomerular filtration rate）以及出生后年龄优化给药剂量。研究共报告2例致死性严重不良事件（均由左心室发育不良综合征（hypoplastic left heart syndrome）导致），但上述事件与研究药物无关。基于本研究数据，地高辛在单心室先天性心脏病患儿中安全性良好。本研究纳入的50例受试者均为已接受手术或复合式Ⅰ期姑息治疗，但尚未接受Ⅱ期手术姑息治疗的单心室先天性心脏病患儿。