Influence of Lopinavir/Ritonavir on Gemfibrozil Disposition in Healthy Subjects

高血压仍然是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的患者。 与PI初治患者相比，PI治疗患者的低密度脂蛋白（LDL）、甘油三酯（TG）和总胆固醇增加。 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，已开始发现心血管并发症。 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HIV感染受试者中，TG通常仍高于正常上限。 这些患者中TG持续升高的一个可能原因是他们的纤维酸治疗的疗效降低，这可能是由未识别的药物相互作用引起的。 纤维酸衍生物通过HIV PI利托那韦诱导的尿苷5-二磷酸-葡萄糖醛酸转移酶（UGT）在肝脏中代谢。 事实上，利托那韦显著降低了由该酶系统代谢的其他药物的血浆浓度40- 50%。 随着UGT活性的诱导，UGT底物（吉非罗齐）的代谢将增加，导致其血浆浓度降低。 非HIV感染受试者的初步数据表明，吉非罗齐血浆浓度降低可能导致药物疗效降低。 尽管事实上，许多HIV感染的高胆固醇血症患者可能正在接受使用纤维酸衍生物的降胆固醇治疗，同时接受包括利托那韦（即洛匹那韦+利托那韦LPV/r）的抗逆转录病毒治疗，但尚未对这两种药物进行联合研究以确定它们是否相互作用。 本研究的目的是描述健康志愿者单次口服600 mg吉非罗齐后，LPV/r对吉非罗齐药代动力学（PK）特征的影响。 在纵向研究设计中，15例受试者将在LPV/r 400/100 mg每日两次治疗13天之前和之后接受吉非罗齐600 mg单次给药。 将在第1天和第14天测定吉非罗齐的药代动力学，并使用student t检验进行比较。 本研究的结果将提供（或反驳）进一步研究的依据，这些研究旨在评估吉非罗齐与利托那韦联合给药时剂量调整的可能性，以最大限度地发挥吉非罗齐的药理学作用。 本研究于2008年3月完成。15名健康志愿者（8名男性）完成了研究。所有研究药物通常耐受良好，无受试者退出研究。洛匹那韦-利托那韦治疗14天后吉非罗齐血药浓度-时间曲线下面积（AUC）与基线相比的几何均值比（GMR，90% CI）为0.59（0.52，0.67）（P < 0.001）。洛匹那韦-利托那韦治疗后，所有15例研究受试者的吉非罗齐AUC均降低（范围：-6%至-74%）。 洛匹那韦-利托那韦治疗14天后，与基线相比，吉非罗齐表观口服清除率（Cl/F）和最大浓度（Cmax）的GMR分别为1.69（1.41，1.97）和0.67（0.49，0.86）（分别为P < 0.0001和0.01）。相反，洛匹那韦-利托那韦给药后吉非罗齐消除半衰期没有变化（P = 0.60），达峰时间也没有变化（P = 0.56）。洛匹那韦/利托那韦显著降低了吉非罗齐的全身暴露量;最可能是由于该联合用药降低了吉非罗齐的吸收。临床医生在确定HIV感染伴高脂血症患者的最佳治疗方法时应考虑这种药物相互作用。这项研究的结果将于2008年10月在华盛顿举行的抗菌药物和化疗跨学科会议上发表。目前正在编写手稿。

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. This study was completed in March, 2008. Fifteen healthy volunteers (8 males) completed the study. All study drugs were generally well-tolerated and no subjects withdrew participation. The geometric mean ratio (GMR, 90% CI) for gemfibrozil area under the plasma concentration-time curve (AUC) after 14 days of lopinavir-ritonavir compared to baseline was 0.59 (0.52, 0.67) (P < 0.001). All 15 study subjects experienced a reduction in gemfibrozil AUC after lopinavir-ritonavir (range: -6% to -74%). The GMRs for gemfibrozil apparent oral clearance (Cl/F) and maximum concentration (Cmax) were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P < 0.0001 and 0.01, respectively). Conversely, gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60) nor did time to maximum concentration (P = 0.56. Lopinavir/ritonavir significantly reduced the systemic exposure of gemfibrozil; most likely due to reduced gemfibrozil absorption with this combination. Clinicians should consider this drug interaction when determining the optimal therapeutic approach to HIV-infected patients with hypertriglyceridemia. Results frrom this investigation will be presented at the Interscience Conference for Antimicrobial Agents and Chemotherapy in Washington DC, October, 2008. A manuscript is currently undergoing preparation.