The Influence of Herbal Supplements on Lopinavir/Ritonavir Pharmacokinetics

草药补充剂对洛匹那韦/利托那韦药代动力学的影响

基本信息

批准号：
8565305
负责人：
Scott Penzak
金额：
--
依托单位：
CLINICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
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/8565305
关键词：
Affect Alternative Medicine Anti-Retroviral Agents Area Awareness CYP3A4 gene Carrier Proteins Cholesterol Clinic Collection Complementary Medicine Confidence Intervals Cytochrome P450 3A4 Data Dose Drug Interactions Drug Kinetics Drug Transport Echinacea Preparation Echinacea purpurea Enzymes Evaluation Failure Garlic Ginkgo biloba Ginseng Preparation HIV HIV Protease Inhibitors Half-Life Hepatic Herb Hypericum perforatum Individual Investigation Laboratories Lopinavir Lopinavir/Ritonavir Mediating Metabolism Midazolam Oral Outpatients P-Glycoprotein Panax ginseng Participant Patients Pharmaceutical Preparations Phenotype Physicians Plasma Property Protease Inhibitor Relative (related person)Reporting Risk Ritonavir Supplementation Time Toxic effect Triglycerides arm base clinically significant design dietary supplements enzyme activity fexofenadine human subject inclusion criteria meetings open label total measurement Bilirubin

项目摘要

Patients with HIV commonly use herbal products and dietary supplements in addition to medications prescribed by their physicians. Up to 73% of patients with HIV have reported using some form of complementary or alternative medicine. As such, the potential for clinically significant drug interactions between herbs and antiretrovirals is becoming increasingly appreciated. Despite this awareness, little is known about the effect of commonly used herbal products, such as echinacea, ginkgo biloba, and ginseng, on antiretroviral pharmacokinetics. Interacting herbal supplements have the potential to alter protease inhibitor (PI) plasma concentrations, as has been shown with St. Johns wort and garlic. Drug interactions may potentially increase antiretroviral concentrations, putting patients at risk for toxicities, or lower drug concentrations, putting patients in jeopardy of antiretroviral failure. The protease inhibitors lopinavir and ritonavir both rely principally on cytochrome P450 (CYP) 3A4 metabolism for their elimination. In addition, both drugs are both substrates for the transport protein p-glycoprotein (P-gp), which may also contribute to their distribution and elimination. The primary purpose of this investigation is to determine whether the herbal supplements Echinacea purpurea, ginkgo biloba, and Panax ginseng alter the pharmacokinetic properties of the HIV protease inhibitor combination lopinavir/ritonavir (LPV/r). Secondary objectives will assess the influence of E. purpurea, G. bilobaextract (GBE), and P. ginseng on (1) CYP3A enzyme activity and (2) P-gp mediated drug transport. This is an open label pharmacokinetic study that will be performed on an outpatient basis. A total of 42 study participants who have met inclusion criteria will be sequentially divided into one of 3 groups, such that 14 subjects each will receive LPV/r alone and in combination with either E. purpurea, G. biloba, or P. ginseng. Subjects will receive single oral doses of fexofenadine 120 mg and midazolam 8 mg followed by plasma collection for determination of baseline CYP3A and P-gp phenotypes (Study Day 1). Between 7 and 28 days after Day 1, subjects will begin taking LPV/r (400mg/100mg twice daily x 29.5 days), returning to clinic on Day 15 of LPV/r for post-dose plasma collection and determination of lopinavir and ritonavir concentrations. On Day 16 participants will begin taking either E. purpurea (800 mg, twice daily), G. biloba extract (120 mg, twice daily), or P. ginseng (500 mg, three times daily) for 28 days. On the 30th day of LPV/r (Day 15 of the herb), subjects will return to clinic where they will take their final LPV/r dose and then have their plasma collected for determination of lopinavir and ritonavir concentrations. On the last day (28th day) of herbal supplementation, participants will return to the clinic for determination of P-gp and 3A phenotypes using single doses of fexofenadine and midazolam as described for Study Day 1. Data from this investigation will determine whether echinacea, ginseng, or ginkgo biloba supplements alter the pharmacokinetics of the protease inhibitor combination lopinavir/ritonavir, and whether or not modulation of CYP3A and/or P-gp contributed to any observed interaction. The first arm of this study, assessing the influence of GBE on lopinavir and ritonavir disposition, has been completed. Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C(max) by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin. CONCLUSIONS: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decreasein midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively. The second arm of this study, assessing the influence of Echinacea purpurea on lopinavir-ritonavir pharmacokinetics, was recently completed. The area under the concentration vs. time curve (90% confidence intervals) from zero to 12 hrs (AUC, 0-12) for lopinavir was 109 (88-131)g*hr/mL before- vs. 105 (81-129) g*hr/mL after Echinacea administration (P = 0.82). Similarly, there were no significant differences (P > 0.05) in lopinavir maximum concentration (Cmax), apparent oral clearance at steady state (Clss/F), and half-life (T ) after Echinacea administration; this also held true for ritonavir pharmacokinetic parameter values pre- and post Echinacea dosing. In summary, two weeks of Echinacea purpurea administration did not alter the steady state pharmacokinetic profiles of lopinavir and ritonavir in healthy human subjects. These data suggest that a pharmacokinetic interaction between Echinacea purpurea and lopinavir-ritonavir is unlikely to occur in HIV-infected individuals taking these products in combination. Data from the third arm of ths study is also complete. The influence of Panax ginseng on CYP3A and P-gp activity was assessed using the probe substrates midazolam and fexofenadine, respectively. We observed significant reductions in midazolam AUC(0.66; 0.55-0.78), half-life (0.71; 0.53-0.90), and Cmax (0.74; 0.56-0.93), and a significant increase in CL/F (1.51; 1.17-1.86) (P < 0.05 for all comparisons) after 28 days of Panax ginseng administration. Conversely, ginseng administration did not affect the pharmacokinetics of fexofenadine. Lastly, plasma lopinavir and ritonavir concentrations were not significantly altered by Panax ginseng administration either (P > 0.05 for all comparisons between pharmacokinetic parameter values before, and after Panax ginseng administration).

艾滋病毒患者除了医生开了药物外，通常还使用草药和饮食补充剂。多达73％的艾滋病毒患者报告使用了某种形式的互补或替代药物。因此，草药和抗逆转录病毒在临床上具有重要的药物相互作用的潜力越来越受到人们的认识。尽管有这种意识，但对常用草药产品的影响，例如紫锥菊，银杏鸟和人参，对抗逆转录病毒药代动力学的影响知之甚少。与St. Johns Wert和Garlic所示，相互作用的草药补充剂有可能改变蛋白酶抑制剂（PI）血浆浓度。药物相互作用可能会增加抗逆转录病毒浓度，使患者处于毒性或降低药物浓度的风险，从而使患者危害抗逆转录病毒衰竭。蛋白酶抑制剂lopinavir和Ritonavir主要依赖于细胞色素P450（CYP）3A4代谢来消除它们。此外，两种药物都是转运蛋白P-糖蛋白（P-GP）的底物，这也可能有助于其分布和消除。这项研究的主要目的是确定草药补充剂紫chin紫，银杏叶和Panax人参是否会改变HIV蛋白酶抑制剂组合lopinavir/ritonavir（LPV/R）的药代动力学特性。次要目标将评估E. purpurea，G。Bilobaextract（GBE）和P. Ginseng对（1）CYP3A酶活性和（2）P-GP介导的药物转运的影响。这是一项开放标签的药代动力学研究，将在门诊的基础上进行。总共符合纳入标准的42名研究参与者将被依次分为3组之一，因此，每个受试者将单独接受LPV/R，并与E. purpurea，G。Biloba或P. Ginseng结合使用。受试者将接受单剂量的Fexofenadine 120 mg和咪达唑仑8 mg，然后收集血浆，用于测定基线CYP3A和P-GP表型（研究第1天）。在第1天后的第7天到28天之间，受试者将开始服用LPV/R（每天两次x 29.5天），在LPV/R的第15天返回诊所进行剂量血浆收集，并确定lopinavir and Ritonavir浓度。在第16天，参与者将开始服用E. purpurea（每天两次，每天两次），G。Biloba提取物（120 mg，每天两次）或P. Ginseng（每天500毫克，每天3次），持续28天。在LPV/R的第30天（草药的第15天），受试者将返回诊所，在那里他们采用最终的LPV/R剂量，然后将其等离子体收集以确定lopinavir和Ritonavir浓度。在研究第1天所述，参与者将使用单剂量的fexofenadine和interymiazolam返回诊所确定P-gp和3a表型，以确定本研究的数据。以及CYP3A和/或P-gp的调节是否有助于任何观察到的相互作用。这项研究的第一臂评估了GBE对Lopinavir和Ritonavir处置的影响。 Lopinavir，Ritonavir和Fexofenadine暴露不受GBE给药的显着影响。但是，相对于基线，GBE分别降低了咪达唑仑AUC（0-核酸）和C（最大）34％（p = 0.03）和31％（p = 0.03）。通常，Lopinavir/Ritonavir和GBE的耐受性良好。异常实验室结果包括肝酶，胆固醇和甘油三酸酯的轻度升高以及总胆红素的轻度到中度增加。结论：我们的结果表明，GBE诱导了CYP3A代谢，如咪达唑仑浓度降低所评估。但是，洛匹那韦的暴露没有变化，这可能是由于利托纳维尔对CYP3A4的有效抑制作用。因此，GBE似乎不太可能减少利托纳维尔促进的蛋白酶抑制剂的暴露，而未促进的蛋白酶抑制剂的浓度可能会受到影响。我们研究的局限性包括单个序列设计以及仅对利托纳维尔促进蛋白酶抑制剂的评估。最近完成了这项研究的第二组，评估了紫旋op紫陶氏紫菜对lopinavir-Ritonavir药代动力学的影响。浓度与时间曲线（90％置信区间）在lopinavir的零至12小时（AUC，0-12）的面积为109（88-131）G*HR/ML之前-105（81-129）G*HR/ML echinacea给药后（P = 0.82）。类似地，洛匹那韦的最大浓度（CMAX），稳态（CLSS/F）的明显口服清除以及紫锥菊给药后的半衰期（T）也没有显着差异（p> 0.05）。对于利托那韦药代动力学参数值前和紫锥菊的剂量值也是如此。总而言之，在健康人类受试者中，两周的紫锥菊给药并没有改变洛匹那韦和利托那韦的稳态药代动力学特征。这些数据表明，在艾希氏二氧紫红葡萄氏紫红蛋白和洛匹那韦 - 利托那韦之间的药代动力学相互作用不太可能在艾滋病毒感染的个体中发生。 THS研究的第三组的数据也已完成。 Panax人参对CYP3A和P-GP活性的影响分别使用探针底物咪达唑仑和fexofenadine评估。我们观察到咪达唑仑AUC（0.66; 0.55-0.78），半寿命（0.71; 0.53-0.90）和CMAX（0.74; 0.74; 0.56-0.93）的显着降低，以及Cl/f（1.51; 1.17-1.86）（P <0.05）（P <0.05 for All Materiss for All Materiss）的28天的cl/f（1.51; 1.17-1.86）显着增加。相反，人参管理不影响fexofenadine的药代动力学。最后，Panax Ginseng给药的血浆lopinavir和Ritonavir浓度也没有显着改变（对于Panax Ginseng给药之前的药代动力学参数值的所有比较，P> 0.05）。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antiviral therapy in patients with hematologic malignancies, transplantation, and aplastic anemia.

DOI：
10.1053/j.seminhematol.2009.03.004
发表时间：
2009-07
期刊：
Seminars in hematology
影响因子：
3.6
作者：
T. Jancel;S. Penzak
通讯作者：
T. Jancel;S. Penzak

Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects.

DOI：
10.1592/phco.30.8.797
发表时间：
2010-08
期刊：
Pharmacotherapy
影响因子：
4.1
作者：
Penzak SR;Robertson SM;Hunt JD;Chairez C;Malati CY;Alfaro RM;Stevenson JM;Kovacs JA
通讯作者：
Kovacs JA

Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants.