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

 描述(由申请者提供)：这是为罗切斯特大学医学中心助理教授、药学博士Charles Venuto申请K23指导的以患者为导向的职业发展奖。韦努托博士在临床研究方面建立了坚实的基础，重点是艾滋病毒抗逆转录病毒药物的临床药理学和临床TRIL方法学。这些培训经历使他成为艾滋病毒、抗逆转录病毒和丙型肝炎病毒(丙型肝炎病毒)抗病毒临床药理学方面的独立研究员，为自己开辟了一条专注而明确的职业道路。丙型肝炎病毒引起的肝病现在已经成为艾滋病毒携带者严重疾病和死亡的主要原因；然而，新的丙型肝炎病毒疗法的治疗进展才刚刚开始在合并感染的人中形成。尽管这些新的直接作用抗病毒药物为合并感染人群带来了有希望的治疗策略，但必须解决一些挑战，以确定其安全性和有效性。药物之间的相互作用、重叠的药物毒性、增加的药物负担和药代动力学(PK)的变异性使得临床研究结论很难从单一感染转化为联合感染。 受感染的患者群体。考虑到这一点，维努托博士的兴趣集中在研究 药物在艾滋病毒和艾滋病毒/丙型肝炎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。这一K23奖项中的培训和研究计划是围绕这样一个假设设计的，即基于模型的药代动力学和药物-药物相互作用研究等计算机工具的替代方法，以及使用临床前和临床试验数据的数据驱动方法，可以用于预测艾滋病毒单一感染者和艾滋病毒/丙型肝炎病毒混合感染者的药物暴露、相互作用潜力和抗病毒效果。这项K23奖将作为一种工具，通过利用NIH赞助的艾滋病临床试验小组网络中的现有基础设施来研究这一假说。此外，还将收集新的试点数据，以比较艾滋病毒单一感染患者和联合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、艾滋病毒临床药理学以及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途径来更多地了解针对艾滋病毒/丙型肝炎患者的新的治疗策略。

 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.