Influence of Lopinavir/Ritonavir on Gemfibrozil Disposition in Healthy Subjects

高脂血症仍然是艾滋病毒感染者的常见问题，特别是那些接受艾滋病毒蛋白酶抑制剂（pi）或核苷逆转录酶抑制剂司他夫定的患者。与未接受pi治疗的个体相比，pi治疗的患者有低密度脂蛋白（LDL）、甘油三酯（TG）和总胆固醇的增加。在接受含pi治疗的患者中，脂质异常的患病率估计为27-57%；此外，心血管并发症也开始显露出来。特别是甘油三酯升高，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。尽管使用纤维酸衍生物，如吉非罗齐进行治疗，但在艾滋病毒感染者中，TGs通常仍高于正常上限。这些患者TGs持续升高的一个可能原因是纤维酸治疗的疗效降低，这可能是由于未被识别的药物-药物相互作用造成的。纤维酸衍生物在肝脏中通过尿苷5-二磷酸-葡萄糖醛酸转移酶（UGT）代谢，这是由HIV PI，利托那韦诱导的。事实上，利托那韦显著降低了经该酶系统代谢的其他药物的血浆浓度40-50%。由于UGT活性被诱导，UGT底物（吉非齐尔）的代谢会增加，导致其血浆浓度下降。非hiv感染受试者的初步数据表明，血浆吉非罗齐浓度降低可能导致药物疗效降低。尽管许多患有高甘油三酯血症的hiv感染患者可能在接受包括利托那韦（即洛匹那韦+利托那韦LPV/r）在内的抗逆转录病毒治疗的同时接受纤维酸衍生物的甘油三酯降低治疗，但尚未对这两种药物联合研究以确定它们是否相互作用。本研究的目的是表征LPV/r对健康志愿者单次口服600 mg吉非罗齐的药代动力学（PK）谱的影响。在一项纵向研究设计中，15名受试者将在LPV/ 400/100 mg，每天两次的13天前后接受单剂量600 mg的吉非齐尔。将在第1天和第14天测定吉非罗齐的药代动力学，并使用学生t检验进行比较。本研究的结果将为进一步的研究提供（或反驳）依据，这些研究旨在评估在与利托那韦联合给药时调整吉非齐齐剂量的可能性，以最大限度地发挥吉非齐齐的药理作用。

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.