Quantitative Pharmacology for Accelerating Drug Development for HIV/HCV Co-Infected Patients

 描述（由申请人提供）：这是罗切斯特大学医学中心助理教授查尔斯·韦努托博士的K23指导型以患者为导向的职业发展奖申请。Venuto博士在临床研究方面建立了坚实的基础，重点是HIV抗逆转录病毒药物的临床药理学和临床试验方法。这些培训经验使他成为一名独立的艾滋病毒抗逆转录病毒和丙型肝炎病毒（HCV）抗病毒临床药理学研究者。由HCV引起的肝脏疾病现已成为HIV感染者严重疾病和死亡的主要原因;然而，新型HCV疗法的治疗进展才刚刚开始在合并感染者中形成。尽管这些新的直接作用的抗病毒药物为合并感染人群带来了有希望的治疗策略，但为了确定其安全性和有效性，必须解决一些挑战。药物间相互作用、重叠的药物毒性、增加的药丸负担和药代动力学（PK）变异性使得临床研究结论难以从单一感染转化为共同感染。 受感染的患者群体。考虑到这一点，Venuto博士的兴趣集中在研究 药物在HIV和HIV/HCV患者中的药代动力学和药效学（PK/PD）模式，并确定这些模式如何影响临床结果。K23奖项中的培训和研究计划是围绕以下假设设计的：替代的计算机工具，如基于模型的药代动力学和药物相互作用研究，以及使用临床前和临床试验数据的数据驱动方法，可用于预测HIV单感染和HIV/HCV合并感染个体中的药物暴露，相互作用潜力和抗病毒作用。这个K23奖将作为一种工具，通过利用NIH赞助的艾滋病临床试验组网络内的现有基础设施来调查这一假设。此外，还将收集新的试点数据，以比较HIV单感染和合并感染患者之间的抗逆转录病毒PK，并验证根据临床试验数据开发的建模工具。动态的研究环境和由临床试验方法学、HIV临床药理学以及PK/PD建模和模拟方面的领导者组成的指导团队将促进每个目标的实现。总之，提出的基于模型的临床药理学方法提供了全面和有效的方法来了解更多关于艾滋病毒/丙型肝炎患者的新兴治疗策略。

 DESCRIPTION (provided by applicant): This is an application for a K23 Mentored Patient-Oriented Career Development Award for Dr. Charles Venuto, PharmD, an assistant professor at the University of Rochester Medical Center. Dr. Venuto has established a strong foundation in clinical research with an emphasis in clinical pharmacology of HIV antiretrovirals and clinical tril methodologies. These training experiences have led to a focused and clear career path towards establishing himself as an independent investigator in HIV antiretroviral and hepatitis C virus (HCV) antiviral clinical pharmacology. Liver disease caused by HCV has now become a leading cause of serious illness and death in people with HIV; however, treatment advances in novel HCV therapies are just beginning to take shape in co-infected individuals. Although these new direct acting antivirals bring promising treatment strategies to the co-infected population, there are challenges that must be addressed in order to establish their safety and effectiveness. Drug-drug interactions, overlapping drug toxicities, increased pill burden, and pharmacokinetic (PK) variability have made it difficult to translate clinical study conclusions from mono-infected to co infected patient populations. With this in mind, Dr. Venuto's interests are focused in studying the pharmacokinetic and pharmacodynamic (PK/PD) patterns of drugs in patients with HIV and HIV/HCV, and identifying how these patterns influence clinical outcomes. The training and research plans within this K23 award have been devised around the hypothesis that alternative in silico tools such as model- based pharmacokinetic and drug-drug interaction studies, and data-driven approaches using preclinical and clinical trial data can be used to predict drug exposure, interaction potential and antiviral effects within HIV mono-infected and HIV/HCV co-infected individuals. This K23 award will serve as a vehicle for investigating this hypothesis by taking advantage of existing infrastructure within the NIH-sponsored AIDS Clinical Trials Group Network. Additionally, new pilot data will also be collected to compare antiretroviral PK between HIV mono- and co-infected patients, and to validate modeling tools developed from the clinical trial data. Dynamic research environments and a mentoring team comprised of leaders in clinical trial methodologies, HIV clinical pharmacology, and PK/PD modeling and simulation will facilitate the achievement of each goal. In conclusion, the model-based clinical pharmacology approaches proposed offer comprehensive and efficient ways to learn more about emerging treatment strategies for HIV/HCV patients.