A Pharmacokinetic Comparison of Sertraline Before and After Bariatric Surgery

描述(由申请人提供)： 这项建议旨在提供一个全面的培训和研究计划，以促进我成为临床药物治疗研究领域的独立研究员的长期职业目标。为了实现这一目标，已经制定了三个短期目标：1)发展进行临床药物治疗研究的高级技能，2)发展药代动力学技能并能够将其应用于减肥外科研究，以及3)发展高级统计分析技能。为了协助实现这些目标，根据他们在这些领域的专长，挑选了一名主要导师和三名共同导师。在与这些导师的合作下，我制定了一个五年的指导和培训计划，以实现每个目标。职业发展活动和研究将在新泽西州法戈的神经精神病学研究所进行。这一职业发展计划包括经常与每位导师举行有组织的会议，以及与每个目标相关的学习目标。培训计划还包括几个拟议的学期长课程和短课程，每个目标至少有一门课程。特别是，培训计划包含相对较高密度的药物动力学领域的课程，鉴于该领域的广度和我在该领域缺乏研究经验，这是必要的。还包括了其他几种培训经验，例如多次研讨会、观察和参加国家会议。减肥外科手术，特别是Roux-en-Y胃旁路手术(RYGBP)，被广泛实施，其使用也在继续增加。这些患者中的大多数在手术前服用多种药物，并在手术后继续服用其中一些药物。然而，RYGBP对大多数药物的药代动力学的影响尚不清楚。药物药代动力学曲线的改变会影响药物的疗效和耐受性。很大比例的减肥手术应聘者在手术前服用抗抑郁药物。与许多其他类别的药物不同，患者通常在手术后随着并发症的解决而停止服用，数据显示，大多数患者仍在继续服用抗抑郁药物。因此，建议进行一项前瞻性的纵向试验，以研究舍曲林在RYGBP术前、术后3个月和12个月的药代动力学参数。通过片剂和液体制剂的相对生物利用度比较，以及对感兴趣的生理变量的纵向评估，本研究还将初步探索产生假想药代动力学变化的潜在机制。通过这项研究积累的经验和数据，再加上通过职业发展计划提供的培训和指导，将使我能够制定一个与减肥手术相关的持续药代动力学研究计划。这将满足我成为临床药物治疗研究的独立研究员的长期职业目标。鉴于新药的不断开发，减肥手术程序随着时间的推移而演变，以及为临床实践建立循证用药建议的需要，这一职业方向应该被证明是持续卓有成效的。 公共卫生相关性： 药物动力学变化会影响药物的疗效和耐受性。鉴于减肥手术后药代动力学变化的数据缺乏，拟议的研究将使用抗抑郁药舍曲林作为试验药物，提供有关这一问题的临床相关信息。

DESCRIPTION (provided by applicant): This proposal has been designed to provide a comprehensive training and research plan which will facilitate my long-term career goal of becoming an independent investigator in the area of clinical pharmacotherapy research. To accomplish this objective, three short-term goals have been developed: 1) To develop advanced skills in conducting clinical pharmacotherapy research, 2) To develop pharmacokinetic skills and to be able to apply them to bariatric surgery research, and 3) To develop advanced statistical analysis skills. To assist in the attainment of these goals, a primary mentor and three co-mentors have been selected based upon their expertise in these areas. In collaboration with these mentors, I have developed a five-year mentoring and training plan to address each goal. The career development activities and research will be carried out at the Neuropsychiatric Research Institute, Fargo, ND. This career development plan includes frequent structured meetings with each of the mentors, along with learning objectives related to each goal. The training plan also includes several proposed semester-long and short-courses, with at least one course directed toward each goal. In particular, the training plan contains a relatively high density of courses within the area of pharmacokinetics, which is necessary given the breadth of this field and my lack of research experience in this area. Several other training experiences have been included, such as multiple seminars, observations, and attendance at national conferences. Bariatric surgery procedures, in particular the Roux-en-Y Gastric Bypass (RYGBP), are widely performed and their use continues to increase. The majority of these patients take [sic] multiple medications prior to surgery and remain [sic] on some of them following surgery. Yet, the influence of RYGBP on the pharmacokinetics of the majority of medications is unknown. Changes in a medication's pharmacokinetic profile can influence the efficacy and tolerability of the medication. A large proportion of bariatric surgery candidates take an antidepressant medication preoperatively. Unlike many other classes of medications which patients often stop after surgery as comorbidities resolve, data show that the majority of patients continue to take antidepressant medication. Thus, a prospective, longitudinal trial is proposed to investigate the pharmacokinetic parameters of sertraline preoperatively and at three and 12 months following RYGBP. Through a relative bioavailability comparison of tablet and liquid sertraline preparations, and through longitudinal assessments of physiological variables of interest, this study will also provide a preliminary exploration of the potential mechanisms which produce the hypothesized pharmacokinetic changes. The experience and the data accumulated through this research, coupled with the training and mentoring provided through the career development plan, will allow me to develop an ongoing program of research in pharmacokinetics related to bariatric surgery. This will satisfy my long-term career goal of becoming an independent researcher in clinical pharmacotherapy research. Given the continual development of new medications, the evolution of bariatric surgery procedures over time, and the need to establish evidence-based medication recommendations for clinical practice, this career direction should prove fruitful on an ongoing basis. PUBLIC HEALTH RELEVANCE: Pharmacokinetic changes can impact the efficacy and tolerability of medications. Given the paucity of data on pharmacokinetic changes following bariatric surgery, the proposed study will provide clinically relevant information concerning this issue using the antidepressant sertraline as a test drug.