Influence of Lopinavir/Ritonavir on Gemfibrozil Disposition in Healthy Subjects

洛匹那韦/利托那韦对健康受试者吉非罗齐分布的影响

• 批准号: 7593059
• 负责人: Scott Penzak
• 金额: $ 2.48万
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593059
• 关键词: Acids; Cardiovascular system; Cholesterol; Coronary Arteriosclerosis; Daily; Data; Development; Diphosphates; Dose; Drug Interactions; Drug Kinetics; Elevation; Enzymes; Gemfibrozil; HIV; HIV Protease Inhibitors; Hyperlipidemia; Hypertriglyceridemia; Individual; Lead; Lipids; Liver; Longitudinal Studies; Lopinavir/Ritonavir; Metabolism; Nucleosides; Oral; Pancreatitis; Patients; Pharmaceutical Preparations; Plasma; Prevalence; Protease Inhibitor; Research Design; Research Personnel; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Stavudine; Students; System; Testing; Transferase; Triglycerides; Upper Limit of Normal; Uridine; Week; antiretroviral therapy; day; drug efficacy; enzyme activity; enzyme substrate; healthy volunteer; low density lipoprotein triglyceride

Hyperlipidemia continues to be a common problem in individuals with HIV, particularly those receiving HIV protease inhibitors (PIs) or the nucleoside reverse transcriptase inhibitor, stavudine. PI-treated patients have been noted to have increases in low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol compared to PI-treatment nave individuals. The prevalence of lipid abnormalities in patients receiving PI-containing therapy has been estimated at 27-57%; moreover, cardiovascular complications have begun to be revealed. Triglyceride elevations, in particular, are not only an independent risk factor for the development of coronary artery disease, but may also lead to pancreatitis. Despite treatment with fibric acid derivatives, such as gemfibrozil, TGs typically remain elevated above the upper limit of normal in HIV-infected subjects. One possible reason for persistently elevated TGs in these patients is reduced efficacy of their fibric acid therapy, which may result from an unrecognized drug-drug interaction. Fibric acid derivatives are metabolized in the liver via uridine 5-diphosphate-glucuronosyl transferase enzymes (UGT), which are induced by the HIV PI, ritonavir. Indeed, ritonavir significantly lowers plasma concentrations of other drugs metabolized by this enzymatic system by 40-50%. As UGT activity is induced, the metabolism of UGT substrates (gemfibrozil) will increase, resulting in a decrease in their plasma concentrations. Preliminary data in non-HIV-infected subjects suggest that reduced plasma concentrations of gemfibrozil are likely to result in reduced efficacy of the drug. Despite the fact that many HIV-infected patients with hypertriglyceridemia are likely to be receiving triglyceride-lowering therapy with a fibric acid derivative while simultaneously receiving antiretroviral therapy that includes ritonavir (i.e. lopinavir + ritonavir LPV/r), these two drugs have not been studied in combination to determine whether or not they interact. The objective of this study is to characterize the impact of LPV/r on the pharmacokinetic (PK) profile of gemfibrozil, after a single 600 mg oral dose, administered to healthy volunteers. In a longitudinal study design, fifteen subjects will receive a single, 600 mg dose of gemfibrozil before and after 13 days of LPV/r 400/100 mg twice daily. Gemfibrozil pharmacokinetics will be determined on days one and 14 and compared using the student t-test. Results from this study will provide (or refute) the rationale for further studies designed to assess the possibility of dose-adjusting gemfibrozil when it is given in combination with ritonavir in order to maximize the pharmacologic effects of gemfibrozil.

在HIV患者中，高脂血症仍然是一个常见问题，尤其是那些接受HIV蛋白酶抑制剂（PI）或核苷逆转录酶抑制剂Stavudine的人。 与PI-治疗中的个体相比，已注意到PI-PI-治疗患者的低密度脂蛋白（LDL），甘油三酸酯（TG）和总胆固醇的增加。 接受含PI疗法的患者脂质异常的患病率估计为27-57％。此外，心血管并发症已经开始揭示。 尤其是甘油三酸酯升高不仅是冠状动脉疾病发展的独立危险因素，而且还可能导致胰腺炎。 尽管用纤维酸衍生物（例如吉菲贝罗齐）进行治疗，但在HIV感染的受试者中，TGS通常仍高于正常上限。 这些患者中TG持续升高的可能原因是其纤维酸治疗的疗效降低，这可能是由于无法识别的药物相互作用而造成的。 纤维酸衍生物通过尿苷5-磷酸葡萄糖基糖基转移酶（UGT）在肝脏中代谢，该酶是由HIV PI，Ritonavir诱导的。 实际上，利托那韦显着降低了该酶系统代谢的其他药物的血浆浓度降低40-50％。 随着UGT活性的诱导，UGT底物（Gemfibrozil）的代谢将增加，从而降低其血浆浓度。 非HIV感染受试者的初步数据表明，吉菲氏菌血浆浓度降低可能导致该药物的疗效降低。 尽管许多事实是，许多受HIV感染的高甘油三酯血症患者可能正在接受纤维酸衍生物降低甘油三酸酯的疗法，同时接受抗逆转录病毒疗法，其中包括RITONAVIR（即lopinavir + Ritonavir + Ritonavir lpv/R），这些药物是否相互作用。 这项研究的目的是表征LPV/R对单一600 mg口服剂量后，对吉菲贝罗齐的药代动力学（PK）剖面的影响，并给予健康志愿者。 在纵向研究设计中，每天两次在LPV/R 400/100毫克之前和之后，有15名受试者将获得一个600毫克的吉菲布罗齐。 Gemfibrozil药代动力学将在第一天和第14天确定，并使用学生t检验进行比较。 这项研究的结果将为进一步的研究提供（或驳斥）基本原理，旨在评估剂量调整后的吉菲贝罗齐的可能性与利托纳维尔（Ritonavir）结合使用，以最大程度地提高gemfibrozil的药理作用。