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.

高脂血症仍然是 HIV 感染者的常见问题，特别是那些接受 HIV 蛋白酶抑制剂 (PI) 或核苷逆转录酶抑制剂司他夫定治疗的患者。 与未接受 PI 治疗的患者相比，接受 PI 治疗的患者的低密度脂蛋白 (LDL)、甘油三酯 (TG) 和总胆固醇有所增加。 据估计，接受含 PI 治疗的患者中血脂异常的发生率为 27-57%；此外，心血管并发症也开始显现。 尤其是甘油三酯升高，不仅是发生冠状动脉疾病的独立危险因素，还可能导致胰腺炎。 尽管使用吉非贝齐等纤维酸衍生物进行治疗，但 HIV 感染者的 TG 通常仍高于正常上限。 这些患者 TG 持续升高的一个可能原因是纤维酸治疗的疗效降低，这可能是由于未识别的药物间相互作用造成的。 纤维酸衍生物在肝脏中通过尿苷 5-二磷酸-葡萄糖醛酸基转移酶 (UGT) 代谢，该酶由 HIV PI（利托那韦）诱导。 事实上，利托那韦可显着降低该酶系统代谢的其他药物的血浆浓度 40-50%。 当UGT活性被诱导时，UGT底物（吉非罗齐）的代谢将增加，导致其血浆浓度降低。 非艾滋病毒感染者的初步数据表明，吉非贝齐血浆浓度降低可能会导致药物疗效降低。 尽管许多患有高甘油三酯血症的 HIV 感染患者可能正在接受纤维酸衍生物的降甘油三酯治疗，同时接受包括利托那韦（即洛匹那韦 + 利托那韦 LPV/r）在内的抗逆转录病毒治疗，但这两种药物尚未联合研究以确定它们是否相互作用。 本研究的目的是确定健康志愿者单次口服 600 mg 剂量后，LPV/r 对吉非贝齐药代动力学 (PK) 的影响。 在一项纵向研究设计中，15 名受试者将在每天两次 LPV/r 400/100 mg 治疗 13 天之前和之后接受单次 600 mg 剂量的吉非贝齐。 吉非罗齐的药代动力学将在第 1 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研究提供（或反驳）理由，进一步研究旨在评估吉非贝齐与利托那韦联合用药时调整剂量的可能性，以最大限度地发挥吉非贝齐的药理作用。