Pharmacokinetic and pharmacogenomic approach to indomethacin therapy in pregnancy

 描述（由申请人提供）：早产（PTB）是全球新生儿发病率和死亡率的主要原因。吲哚美辛已被广泛用于自发性早产（sPTL）患者作为宫缩抑制剂，以延迟分娩和延长妊娠。然而，用于安胎的吲哚美辛剂量是基于从试验和临床实践中获得的经验，而不是严格的药代动力学（PK）/药效学（PD）研究。我们实验室获得的初步数据显示，与非西班牙裔白色孕妇相比，非裔美国孕妇的吲哚美辛表观清除率显著更高。此外，在非裔美国人中，妊娠34周前分娩的女性与34周后分娩的女性相比，吲哚美辛的清除率更高。根据文献，在非裔美国女性中观察到的吲哚美辛清除率较高可归因于较高水平的雌二醇（可诱导代谢吲哚美辛的主要酶CYP 2C 9的活性）以及CYP 2C 9基因多态性。因此，我们假设孕中期的雌二醇水平和CYP 2C 9多态性影响吲哚美辛的PK，并随后影响PTB风险患者对吲哚美辛治疗的反应。（1）确定吲哚美辛在有PTB风险的孕妇中的PK及其对降低妊娠34周前PTB发生率的PD作用，以及PK与次级母体/胎儿/新生儿临床结果之间的任何关联;（2）研究孕中期母体雌二醇水平和CYP 2C 9基因多态性对吲哚美辛向O-去甲基吲哚美辛转化的影响;（3）建立吲哚美辛在PTB高危人群中的群体PK/PD模型（妊娠18-32周），以便基于协变量（如人种/种族、CYP 2C 9基因型、胎龄、雌二醇水平、吸烟状况、体重指数（BMI）。我们将招募300名受试者参加一项前瞻性机会性PK研究，该研究旨在将吲哚美辛的PK、患者基因型和临床结局相关联。我们将合并给药、采样、人口统计学和临床信息与药物浓度数据，并使用群体PK方法学，通过非线性混合效应模型分析数据。个体内和个体间差异的量化允许识别协变量（例如，CYP 2C 9基因型、雌二醇水平、BMI等）可以解释变异性并影响药物暴露。这些 协变量，如果显著的话，则可以在将来用于优化处于PTB风险的个体患者的剂量。实现个体化吲哚美辛治疗的这一目标可能对临床实践产生重大影响，并改善孕产妇和新生儿结局。

 DESCRIPTION (provided by applicant): Preterm birth (PTB) is a major cause of neonatal morbidity and mortality worldwide. Indomethacin has been widely used in patients with spontaneous preterm labor (sPTL) as a tocolytic in order to delay delivery and prolong pregnancy. However, the dose of indomethacin used for tocolysis is based on experience gained from trials and clinical practice and not from rigorous pharmacokinetic (PK)/pharmacodynamic (PD) studies. Pilot data obtained in our laboratory revealed significantly higher apparent clearance of indomethacin in African American pregnant women as compared to White non-Hispanic pregnant women. Furthermore, among African Americans, women who delivered before 34 weeks of gestation had higher clearance of indomethacin as compared to women who delivered after 34 weeks. According to the literature, the higher clearance of indomethacin observed in African American women could be attributed to higher levels of estradiol that may induce activity of the major enzyme CYP2C9 metabolizing indomethacin, as well as to polymorphisms of the CYP2C9 gene. Therefore, we hypothesize that estradiol levels at mid-pregnancy and CYP2C9 polymorphisms affect the PK of indomethacin, and subsequently, the response to indomethacin therapy in patients at risk of PTB. This hypothesis will be tested with the following specific aims: (1) Determine the PK of indomethacin in pregnant women at risk of PTB and its PD effects on reducing the rate of PTB before 34 weeks of gestation, as well as any associations between the PK and secondary maternal/fetal/neonatal clinical outcomes; (2) Determine the effects of maternal levels of estradiol in mid-pregnancy and CYP2C9 polymorphisms on indomethacin biotransformation to O-desmethylindomethacin in pregnant patients; (3) Construct a population PK/PD model of indomethacin in patients at risk of PTB (18-32 weeks of gestation) in order to optimize the dose and the dosing frequency for indomethacin prescribed to each individual based on covariates such as race/ethnicity, CYP2C9 genotype, gestational age, estradiol levels, smoking status, and body mass index (BMI). We will enroll 300 subjects in a prospective opportunistic PK study designed to correlate the PK of indomethacin, patient genotype, and clinical outcomes. We will merge dosing, sampling, demographic, and clinical information with the drug concentration data and use population PK methodologies to analyze the data using nonlinear mixed effect modeling. Quantification of the differences within and between individuals allows for identification of covariates (e.g., CYP2C9 genotype, estradiol levels, BMI, etc.) that can explain variability and affect drug exposure. These covariates, if significant, can then be used in the future to optimize dosing in individual patient at risk for PTB. Achieving this goal of individualized indomethacin therapy could have a significant impact on clinical practice and improve maternal and neonatal outcomes.