Protocol Deviation in Pharmacokinetics of Sildenafil in Premature Infants

Protocol Deviation data
Study Description
This was a phase I, open-label, pharmacokinetic (PK) study with a primary objective of determining PK of sildenafil in premature infants. The trial enrolled 25 premature infants ≤28 weeks gestational age (GA) who were receiving sildenafil per local standard of care at doses between 0.5-2.25 mg/kg in cohort 1, as well as 9 premature infants ≤28 weeks GA and postnatal age range 7-40 days who received a single intravenous dose of sildenafil 0.25 mg/kg or 0.125 mg/kg in cohort 2. A population PK model of sildenafil and metabolite N-desmethyl sildenafil (DMS) was developed. Fluconazole, a CYP3A4 inhibitor, was the only covariate found to explain a significant amount of the variability in sildenafil clearance. Although there is no widely accepted exposure target for sildenafil in the setting of bronchopulmonary dysplasia, simulated exposures obtained here are in agreement with previous population PK analysis performed in infants. Includes 25 enrolled premature infants who were receiving sildenafil per local standard of care in cohort 1, and 9 enrolled premature infants who received a single intravenous dose of sildenafil in cohort 2.

方案偏离数据集
研究概况
本研究为一项I期开放标签药代动力学（pharmacokinetic, PK）研究，首要目标为明确西地那非在早产婴儿中的药代动力学特征。本试验队列1纳入25名胎龄（gestational age, GA）≤28周的早产婴儿，这些患儿按照当地诊疗常规接受西地那非治疗，给药剂量为0.5~2.25 mg/kg；队列2则纳入9名胎龄≤28周、出生后年龄为7~40天的早产婴儿，受试者单次静脉给予西地那非0.25 mg/kg或0.125 mg/kg。研究人员构建了西地那非及其代谢产物去甲基西地那非（N-desmethyl sildenafil, DMS）的群体药代动力学模型。氟康唑作为CYP3A4抑制剂，是唯一被证实可显著解释西地那非清除率变异的协变量。尽管目前尚无支气管肺发育不良（bronchopulmonary dysplasia, BPD）场景下西地那非的公认暴露靶标，但本研究获得的模拟暴露数据与既往针对婴儿开展的群体药代动力学分析结果一致。本数据集包含队列1中25名按当地诊疗常规接受西地那非治疗的入组早产婴儿，以及队列2中9名接受单次静脉西地那非给药的入组早产婴儿。