Supplementary Material for: Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?

<b><i>Introduction:</i></b> Oral ibuprofen is more effective than intravenous (IV) ibuprofen for closure of a patent ductus arteriosus (PDA). This study explored whether higher concentrations of the biologically active S-enantiomer or increased R- to S-conversion following oral dosing could explain this finding. <b><i>Methods:</i></b> Two datasets containing 370 S- and R-ibuprofen concentrations from 95 neonates with PDA treated with oral (<i>n</i> = 27, 28%) or IV ibuprofen were analyzed using nonlinear mixed effects modeling. Concentration-time profiles in typical neonates were explored and compared in different dosing or R- to S-conversion scenarios. <b><i>Results:</i></b> Postnatal age (PNA), gestational age (GA), and being small for GA impacted S- and R-ibuprofen clearance. Upon oral dosing, S-ibuprofen concentrations were lower compared to IV ibuprofen for a large part of the dosing interval. We could show that R- to S-conversion will not exceed 45%. Exploration of a 30% presystemic R- to S-conversion resulted in a 25–32% increase in S-ibuprofen exposure following oral administration with AUC_72h values varying between 700–2,213 mg*h/L (oral) and 531–1,762 (IV) for the standard or 1,704–2,893 (oral) and 1,295–2,271 mg*h/L (IV) for PNA-based dosing. <b><i>Discussion:</i></b> The absence of higher S-ibuprofen concentrations does not support a beneficial concentration-time profile after oral dosing. While a fraction of up to 45% presystemic R- to S-conversion could not be ruled out, the impact of such a low conversion might be only relevant for the standard but not high dosing regimens, considering reported exposure-response targets. Perhaps, the lack of high peak concentrations observed following IV dosing may play a role in the observed effects upon oral dosing.

**<i>引言：</i>** 口服布洛芬在闭合动脉导管未闭（patent ductus arteriosus, PDA）方面的效果优于静脉注射（intravenous, IV）布洛芬。本研究旨在探索，究竟是口服给药后体内具有生物活性的S对映体浓度更高，还是R型向S型的转化增加，从而解释这一临床现象。**<i>方法：</i>** 本研究对两个数据集展开分析，纳入95名接受口服（n=27，占比28%）或静脉注射布洛芬治疗的动脉导管未闭新生儿，其体内S-、R-布洛芬的浓度数据共计370组。研究采用非线性混合效应模型进行数据分析，并针对不同给药方案或R型向S型转化情景，对典型新生儿体内的浓度-时间曲线进行探索与对比。**<i>结果：</i>** 出生后年龄（postnatal age, PNA）、胎龄（gestational age, GA）以及小于胎龄儿状态，均会对S-、R-布洛芬的清除率产生影响。口服给药后，在给药间隔的大部分时段内，S-布洛芬的血药浓度均低于静脉给药组。本研究证实，R型向S型的转化比例不会超过45%。当预设30%的系统前R型向S型转化时，口服给药后的S-布洛芬暴露量会增加25%~32%；其中标准给药方案下，口服给药的72小时曲线下面积（AUC₇₂h）介于700~2213 mg·h/L，静脉给药组为531~1762 mg·h/L；而基于出生后年龄调整给药方案时，口服给药组的AUC₇₂h为1704~2893 mg·h/L，静脉给药组为1295~2271 mg·h/L。**<i>讨论：</i>** 口服给药后并未出现更高的S-布洛芬血药浓度，这一结果并不支持其具有更优的浓度-时间曲线获益。尽管不能排除存在最高可达45%的系统前R型向S型转化，但结合已报道的暴露-反应目标，如此低的转化比例可能仅对标准给药方案有影响，而对高剂量给药方案无显著作用。或许，静脉给药后观察到的高峰浓度缺失，是口服给药产生上述疗效的潜在影响因素。