Shaffer Christopher L, Gal Peter, Ransom J Laurence, Carlos Rita Q, Smith McCrae S, Davey Andrew M, Dimaguila Mary Ann V T, Brown Yvonne L, Schall Stewart A
Greensboro Area Health Eduction Center and the Department of Neonatal Medicine, Women's Hospital of Greensboro, University of North Carolina at Chapel Hill, Greenboro, NC, USA.
Crit Care Med. 2002 Feb;30(2):343-8. doi: 10.1097/00003246-200202000-00013.
To determine patent ductus arteriosus (PDA) closure rates, and indomethacin (INDO) toxicity rates in neonates dosed with INDO using an individualized pharmacokinetic/pharmacodynamic (PK/PD) dosing approach. In addition, develop PD curves evaluating dose-response and concentration-response relationships for closure and renal toxicity, especially in select subgroups historically known as "poor responders" (<1000 g and > or = 10 days postnatal age).
Prospective, cohort study.
Level III neonatal intensive care unit.
One hundred thirty-nine patients receiving 151 courses of INDO for PDA closure were evaluated.
Patients initially received 0.25 mg/kg of INDO, followed immediately by 1 mg/kg of furosemide. INDO concentrations were obtained 2 hrs and 8 hrs after the dose and were assayed using high-performance liquid chromatography. Individualized PK parameters were calculated with subsequent INDO dosing based on the individualized PK variables to increase trough serum concentrations by 0.3-0.5 mg/L.
Ductal closure was successful in 127 patients (91%). Renal toxicity occurred in 21 (15%) patients and was temporary and reversible. No significant differences in response rates based on treatment weight or postnatal age were observed. PD curves were similar for neonates <1000 g vs. > or = 1000 g. PD curves were also similar for neonates with postnatal age <10 days vs. > or = 10 days. Statistically significant differences were noted between neonates categorized for postnatal age <10 days vs. > or = 10 days in total days of therapy (1.8 vs. 2.3 days), total number of doses required to close PDA (3.5 vs. 5.6 doses), critical INDO dose (0.9 vs. 1.4 mg/kg), critical INDO concentration (1.9 vs. 1.4 mg/L), and critical dose/critical concentration ratio (0.52 vs. 2.2).
These findings support the hypothesis that the poor PDA closure rates with INDO for neonates >10 days postnatal age are the result of pharmacokinetic differences only and that weight does not impact response rates. Individualized pharmacokinetic/pharmacodynamic dosing of INDO continues to achieve higher closure rate than current dosing standards. Patients historically known as poor responders significantly benefit from this dosing approach.
采用个体化药代动力学/药效学（PK/PD）给药方法，确定使用吲哚美辛（INDO）治疗的新生儿动脉导管未闭（PDA）的闭合率以及吲哚美辛的毒性率。此外，绘制药效学曲线，评估闭合及肾毒性的剂量-反应和浓度-反应关系，尤其是在历史上被称为“反应不佳者”（出生体重<1000 g且出生后年龄≥10天）的特定亚组中。
前瞻性队列研究。
三级新生儿重症监护病房。
对139例接受151疗程INDO治疗以闭合PDA的患者进行评估。
患者最初接受0.25 mg/kg的INDO，随后立即给予1 mg/kg的呋塞米。给药后2小时和8小时采集INDO浓度，并使用高效液相色谱法进行测定。根据个体化PK变量计算个体化PK参数，并据此进行后续INDO给药，以使谷浓度血清浓度升高0.3 - 0.5 mg/L。
127例患者（91%）动脉导管成功闭合。21例（15%）患者发生肾毒性，且为暂时性和可逆性。未观察到基于治疗体重或出生后年龄的反应率有显著差异。出生体重<1000 g与≥1000 g的新生儿的药效学曲线相似。出生后年龄<10天与≥10天的新生儿的药效学曲线也相似。在出生后年龄<10天与≥10天的新生儿之间，观察到治疗总天数（1.8天对2.3天）、闭合PDA所需的总剂量数（3.5剂对5.6剂）、临界INDO剂量（0.9 mg/kg对1.4 mg/kg）、临界INDO浓度（1.9 mg/L对1.4 mg/L）以及临界剂量/临界浓度比值（0.52对2.2）存在统计学显著差异。
这些发现支持以下假设，即出生后年龄>10天的新生儿使用INDO时PDA闭合率不佳仅是药代动力学差异的结果，且体重不影响反应率。与当前给药标准相比，INDO个体化药代动力学/药效学给药持续实现更高的闭合率。历史上被称为反应不佳者的患者显著受益于这种给药方法。
