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

• 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
• 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

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).

除了医生开出的药物外，艾滋病毒患者通常还使用草药产品和膳食补充剂。 高达 73% 的 HIV 患者报告使用某种形式的补充或替代医学。 因此，草药和抗逆转录病毒药物之间具有临床意义的药物相互作用的潜力越来越受到人们的重视。 尽管有这样的认识，但人们对常用草药产品（如紫锥菊、银杏和人参）抗逆转录病毒药代动力学的影响知之甚少。 相互作用的草药补充剂有可能改变蛋白酶抑制剂 (PI) 的血浆浓度，圣约翰草和大蒜就已证明这一点。 药物相互作用可能会增加抗逆转录病毒浓度，使患者面临中毒风险，或降低药物浓度，使患者面临抗逆转录病毒治疗失败的危险。蛋白酶抑制剂洛匹那韦和利托那韦均主要依靠细胞色素 P450 (CYP) 3A4 代谢来消除。 此外，这两种药物都是转运蛋白p-糖蛋白（P-gp）的底物，这也可能有助于它们的分布和消除。 本研究的主要目的是确定草药补充剂紫锥菊、银杏叶和人参是否会改变 HIV 蛋白酶抑制剂组合洛匹那韦/利托那韦 (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，将在门诊进行。 总共 42 名符合纳入标准的研究参与者将被依次分为 3 组中的一组，这样每组 14 名受试者将单独接受 LPV/r 治疗，并与 E. purpurea、G. biloba 或 P. ginseng 联合治疗。受试者将接受单次口服剂量的非索非那定 120 mg 和咪达唑仑 8 mg，然后收集血浆以确定基线 CYP3A 和 P-gp 表型（研究第 1 天）。 第 1 天后 7 至 28 天之间，受试者将开始服用 LPV/r（400mg/100mg，每日两次 x 29.5 天），并在 LPV/r 第 15 天返回诊所进行给药后血浆收集并测定洛匹那韦和利托那韦浓度。 第 16 天，参与者将开始服用 E. purpurea（800 毫克，每天两次）、银杏提取物（120 毫克，每天两次）或人参（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，在那里他们将服用最终的LPV/r剂量，然后收集血浆以测定洛匹那韦和利托那韦的浓度。 在草药补充剂的最后一天（第 28 天），参与者将返回诊所，使用单剂量的非索非那定和咪达唑仑测定 P-gp 和 3A 表型，如研究第 1 天所述。这项调查的数据将确定是否紫锥菊、人参或银杏叶补充剂会改变蛋白酶抑制剂组合洛匹那韦/利托那韦的药代动力学，以及是否调节CYP3A 和/或 P-gp 促成了任何观察到的相互作用。 该研究的第一部分评估了 GBE 对洛匹那韦和利托那韦处置的影响，现已完成。 GBE 给药对洛匹那韦、利托那韦和非索非那定的暴露没有显着影响。然而，相对于基线，GBE 使咪达唑仑 AUC(0-无穷大)和 C(max) 分别降低 34% (p = 0.03) 和 31% (p = 0.03)。一般来说，洛匹那韦/利托那韦和 GBE 的耐受性良好。实验室结果异常包括肝酶、胆固醇和甘油三酯轻度升高，以及总胆红素轻度至中度升高。结论：我们的结果表明，GBE 诱导 CYP3A 代谢，通过咪达唑仑浓度的降低来评估。然而，洛匹那韦的暴露量没有变化，可能是由于利托那韦对 CYP3A4 的有效抑制。因此，GBE 似乎不太可能减少利托那韦增强的蛋白酶抑制剂的暴露，而未增强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一序列设计和仅评估利托那韦增强的蛋白酶抑制剂。 该研究的第二部分最近完成，评估紫锥菊对洛匹那韦-利托那韦药代动力学的影响。洛匹那韦从零到 12 小时（AUC，0-12）的浓度与时间曲线下面积（90% 置信区间）为 109 (88-131)g*hr/mL，对比之前为 105 (81-129) ) 紫锥菊给药后 g*hr/mL (P = 0.82)。同样，紫锥菊给药后洛匹那韦最大浓度（Cmax）、稳态表观口服清除率（Clss/F）和半衰期（T）也没有显着差异（P > 0.05）；这对于紫锥菊给药前后的利托那韦药代动力学参数值也适用。总之，服用紫锥菊两周并没有改变洛匹那韦和利托那韦在健康人类受试者中的稳态药代动力学特征。这些数据表明，在合并服用紫锥菊和洛匹那韦-利托那韦的 HIV 感染者中，不太可能发生这些产品之间的药代动力学相互作用。 该研究第三组的数据也已完成。分别使用探针底物咪达唑仑和非索非那定评估人参对 CYP3A 和 P-gp 活性的影响。我们观察到咪达唑仑 AUC（0.66；0.55-0.78）、半衰期（0.71；0.53-0.90）和 Cmax（0.74；0.56-0.93）显着降低，CL/F 显着增加（1.51；1.17-1.86） ）（所有比较 P < 0.05）28 天后人参管理。 相反，服用人参并不影响非索非那定的药代动力学。最后，人参给药也没有显着改变血浆洛匹那韦和利托那韦浓度（人参给药前后药代动力学参数值之间的所有比较P>0.05）。

项目成果

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

人参对健康参与者细胞色素 P450 (CYP)3A 和 P-糖蛋白 (P-gp) 活性的影响。

• 发表时间: 2012-06
• 影响因子: 2.9
• 作者: Malati, Christine Y;Robertson, Sarah M;Hunt, Jennifer D;Chairez, Cheryl;Alfaro, Raul M;Kovacs, Joseph A;Penzak, Scott R
• 通讯作者: Penzak, Scott R

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

血液系统恶性肿瘤、移植和再生障碍性贫血患者的抗病毒治疗。

• 发表时间: 2009-07
• 影响因子: 3.6
• 作者: Jancel, Timothy;Penzak, Scott R
• 通讯作者: Penzak, Scott R

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

紫锥菊显着诱导细胞色素 P450 3A 活性，但不会改变健康受试者中洛匹那韦-利托那韦的暴露量。

• 发表时间: 2010-08
• 影响因子: 4.1
• 作者: Penzak, Scott R;Robertson, Sarah M;Hunt, Jennifer D;Chairez, Cheryl;Malati, Christine Y;Alfaro, Raul M;Stevenson, James M;Kovacs, Joseph A
• 通讯作者: Kovacs, Joseph A