Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life.
Developmental pharmacokinetics of indomethacin in preterm neonates: Severely decreased drug clearance in the first week of life.
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DOI：
10.1002/psp4.12881
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发表时间：
2023-01
影响因子：
3.5
通讯作者：
Lewis, Tamorah
中科院分区：
文献类型：
--
作者：
Krzyzanski, Wojciech;Stockard, Bradley;Gaedigk, Andrea;Scott, Allison;Nolte, Whitney;Gibson, Kim;Leeder, J. Steven;Lewis, Tamorah
吲哚美辛通常用于早产儿，用于预防颅内出血和关闭异常开放的心脏血管。由于生物医学的进步，在新生儿重症监护病房环境中接受该药物治疗的婴儿在治疗时变得更年轻、更小、更不成熟(更早产)。为了开发药物动力学(PK)模型来辅助未来的给药，我们设计了一项前瞻性队列研究，以表征动态变化的患者群体中的吲哚美辛PK。使用NONMEM创建了人口PK基础模型，并在主要发展队列中开发了协变量模型，随后在验证队列中测试了准确性。出生后年龄是肝脏清除量(CLH)和肾脏清除量(CLR)的重要协变量。总清除量的典型值(CL，CLR和CLH之和)为3.09 m l/h，表示为CL/W中位数=33.96 m l/h/kg，其中W T中位数为中位体重。CLR和CLH的受试者间变异分别为61%和207%。分布体积的典型值Vp=366 m l(Vp/W中位数n=0 470 m l/kg)，其对象间变异为38.8%。半衰期为82.1小时。与之前研究的更成熟和更年长的早产人群相比，吲哚美辛CL在当代人群中的水平相当低。模型知晓的精确给药结合了体重以外的其他重要协变量，为经历快速变化的易感患者提供了个性化给药的机会。
Indomethacin is used commonly in preterm neonates for the prevention of intracranial hemorrhage and closure of an abnormally open cardiac vessel. Due to biomedical advances, the infants who receive this drug in the neonatal intensive care unit setting have become younger, smaller, and less mature (more preterm) at the time of treatment. To develop a pharmacokinetics (PK) model to aid future dosing, we designed a prospective cohort study to characterize indomethacin PK in a dynamically changing patient population. A population PK base model was created using NONMEM, and a covariate model was developed in a primary development cohort and subsequently was tested for accuracy in a validation cohort. Postnatal age was a significant covariate for hepatic clearance (CLH) and renal clearance (CLR). The typical value of the total clearance (CL, the sum of CLR and CLH) was 3.09 ml/h and expressed as CL/WTmedian = 3.96 ml/h/kg, where WTmedian is the median body weight. The intersubject variability of CLR and CLH were 61% and 207%, respectively. The typical value of the volume of distribution V p = 366 ml (V p/WTmedian = 470 ml/kg), and its intersubject variability was 38.8%. Half‐life was 82.1 h. Compared with more mature and older preterm populations studied previously, indomethacin CL is considerably lower in this contemporary population. Model‐informed precision dosing incorporating important covariates other than weight alone offers an opportunity to individualize dosing in a susceptible patient undergoing rapid change.
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DOI：
10.1124/jpet.103.060137
发表时间：
2004-03-01
影响因子：
3.5
作者：
Koukouritaki, SB;Manro, JR;Hines, RN
通讯作者：
Hines, RN
影响因子：
6.7
作者：
Gaedigk A;Casey ST;Whirl-Carrillo M;Miller NA;Klein TE
通讯作者：
Klein TE
DOI：
10.1136/fn.88.6.f472
发表时间：
2003-11-01
影响因子：
4.4
作者：
Macdonald, PD;Ross, SRM;Young, D
通讯作者：
Young, D
影响因子：
2
作者：
Doshi, Harshit;Shukla, Samarth;Donda, Keyur
通讯作者：
Donda, Keyur
影响因子：
4.1
作者：
Gaedigk, Andrea;Boone, Erin C.;Scherer, Steven E.;Lee, Seung-been;Numanagic, Ibrahim;Sahinalp, Cenk;Smith, Joshua D.;McGee, Sean;Radhakrishnan, Aparna;Qin, Xiang;Wang, Wendy Y.;Farrow, Emily G.;Gonzaludo, Nina;Halpern, Aaron L.;Nickerson, Deborah A.;Miller, Neil A.;Pratt, Victoria M.;Kalman, Lisa, V
通讯作者：
Kalman, Lisa, V