Pharmacokinetic and pharmacogenomic approach to indomethacin therapy in pregnancy

 描述(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)患者的宫缩，以延迟分娩和延长妊娠。然而，用于宫缩的吲哚美辛的剂量是基于从试验和临床实践中获得的经验，而不是来自严格的药代动力学(PK)/药效学(PD)研究。我们实验室获得的初步数据显示，与非西班牙裔白人孕妇相比，非洲裔美国孕妇对吲哚美辛的表观清除量明显更高。此外，在非裔美国人中，怀孕34周前分娩的女性比怀孕34周后分娩的女性对吲哚美辛的清除量更高。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能归因于较高的雌二醇水平，这可能导致代谢吲哚美辛的主要酶CYP2C9的活性，以及CYP2C9基因的多态性。因此，我们假设孕中期的雌二醇水平和细胞色素P2C9基因的多态会影响吲哚美辛的PK，进而影响有肺结核风险的患者对吲哚美辛治疗的反应。这一假设将以以下具体目标进行检验：(1)确定有肺结核危险的孕妇中吲哚美辛的PK及其在妊娠34周前降低肺结核发病率的PD效应，以及PK与继发的母体/胎儿/新生儿临床结局之间的关系；(2)确定孕中期母体雌二醇水平和CYP2C9基因多态性对孕妇吲哚美辛生物转化为O-脱甲基吲哚美辛的影响；(3)建立肺结核高危人群(孕18~32周)吲哚美辛的PK/PD模型，以种族/民族、CYP2C9基因、胎龄、雌二醇水平、吸烟状况、体重指数(BMI)等协变量为基础，优化吲哚美辛给药剂量和给药频率。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与患者的基因型别和临床结果相关联。我们将把剂量、抽样、人口统计和临床信息与药物浓度数据合并，并使用总体PK方法通过非线性混合效应建模来分析数据。量化个体内部和个体之间的差异可以识别协变量(例如，CYP2C9基因、雌二醇水平、BMI等)。这可以解释变异性并影响药物暴露。这些 如果协变量显著，那么未来可以使用协变量来优化患肺结核风险患者的剂量。实现这一个体化吲哚美辛治疗的目标可能会对临床实践产生重大影响，并改善产妇和新生儿的结局。

 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.