Individualization of nifedipine dosing for preterm labor

描述（由申请人提供）：项目摘要/摘要早产是新生儿发病率和死亡率的主要原因。个性化治疗选择的证据，个性化医疗的关键租户，是缺乏在产科医学的许多领域，包括早产的治疗选择。将临床药理学的主要组成部分，包括药物遗传学，药代动力学和定量模型，纳入产科研究，丰富了个性化药物选择和给药的能力。的目标 本K23提案旨在为申请人提供开发特定于产科人群的定量药理学模型所需的高级培训和专业知识。候选人莎拉·昆尼博士哲学博士、是印第安纳州大学医学院（IUSM）妇产科的临床药理学家和助理研究教授。Quinney博士的职业目标是将联合收割机实验室和临床数据结合到定量药理学模型中，以优化孕妇的药物治疗。IUSM拥有强大的学术环境，具有强大的临床研究历史，并致力于指导年轻教师。本提案的导师和顾问将为昆尼博士的职业发展带来相关领域的优势。主要导师，医学博士大卫弗洛克哈特博士，博士，是一位国际公认的临床药理学家，致力于培训翻译研究人员。妇产科在IUSM的部门是家庭对一个特殊的OB/GYN住院医师计划，并具有良好的资源转化研究，包括临床研究助理，可提供给医生既定的工作人员。中心 计算生物学和生物信息学（CCBB）提供了完成提案所需的计算资源。拟议的研究的中心假设是，硝苯地平治疗可以优化一种新的药代动力学/药效学模型，使临床医生选择一个最佳的硝苯地平给药方案。将进行一项临床试验，以检验以下假设：暴露于较高硝苯地平血浆浓度的妇女更有可能对硝苯地平安胎反应，并延迟分娩至少48小时。将检测硝苯地平途径基因（如CYP 3A 4、CYP 3A 5、CACNA 1C和CACN 1C）的药物遗传学变异与硝苯地平的宫缩抑制反应的相关性。其次，利用硝苯地平代谢的体外数据和临床研究的结果，将开发一个包含患者特异性协变量的定量模型，目的是通过更个性化的治疗来确定硝苯地平治疗早产的最佳个体化给药方案。这项研究是有意义的，了解与硝苯地平的可变反应相关的因素，可以改善早产的治疗。此外，本研究将为定量模型的建立奠定基础 用于治疗早产和其他妊娠条件的其他药物，以及候选人在产科药理学方面的成功职业生涯。

DESCRIPTION (provided by applicant): Project Summary/Abstract Preterm labor is a major cause of neonatal morbidity and mortality. Evidence for individualized therapy choice, a key tenant of personalized medicine, is lacking in many areas of obstetric medicine, including in the treatment choices for preterm labor. Incorporating principle components of clinical pharmacology, including pharmacogentics, pharmacokinetics, and quantitative models, into obstetrical research enriches the ability to individualize drug choice and dosing. The objective of this K23 proposal is to provide the advanced training and expertise necessary for the applicant to develop quantitative pharmacology models specific to the obstetric population. The candidate, Dr. Sara Quinney, Pharm.D., Ph.D., is a clinical pharmacologist and Assistant Research Professor in the Department of Obstetrics and Gynecology at the Indiana University School of Medicine (IUSM). Dr. Quinney's career goal is to combine laboratory and clinical data into quantitative pharmacometric models to optimize drug therapy in pregnant women. IUSM hosts a robust academic environment with a strong history of clinical research and a commitment to mentoring young faculty members. The mentors and advisors to this proposal will bring strengths in the areas pertinent to Dr. Quinney's career development. The primary mentor, Dr. David Flockhart, M.D., Ph.D., is an internationally recognized clinical pharmacologist who has shown a commitment to training translational investigators. The Department of Obstetrics and Gynecology at IUSM is home to an exceptional OB/GYN residency program and has excellent resources for translational research, including an established staff of clinical research assistants that are available to Dr. Quinney. The Center for Computational Biology and Bioinformatics (CCBB) provides access to computational resources needed for the completion of the proposal. The central hypothesis of the proposed research study is that nifedipine treatment can be optimized by a novel pharmacokinetic/ pharmacodynamic model that allows clinicians to select an optimum dosing regimen for nifedipine. A clinical trial will be conducted to test the hypothesis that women exposed to higher plasma concentrations of nifedipine are more likely to respond to nifedipine tocolysis and delay delivery at least 48 hours. Pharmacogenetic variations in nifedipine pathway genes, e.g. CYP3A4, CYP3A5, CACNA1C, and CACN1C, will be tested for association with tocolytic response to nifedipine. Secondly, using in vitro data on nifedipine metabolism and the results of the clinical study, a quantitative model that incorporates patient-specific covariates will be developed with the aim to of identifying optimal, individualized dosing regimens of nifedipine for preterm labor through more individualized treatment. This study is significant in that understanding of the factors associated with the variable response to nifedipine can improve the treatment of preterm labor. In addition, this study will lay the foundation for quantitative models of other drugs used in the treatment of preterm labor and other conditions of pregnancy, and for a successful career in obstetrical pharmacology for the candidate.