The Influence of Herbal Supplements on Lopinavir/Ritonavir Pharmacokinetics

除了医生开的药物外，艾滋病毒患者通常还使用草药产品和膳食补充剂。高达73%的艾滋病毒感染者报告使用某种形式的补充或替代药物。因此，草药和抗逆转录病毒药物之间潜在的具有临床意义的药物相互作用越来越受到重视。尽管有这种认识，但人们对常用草药产品（如紫锥菊、银杏叶和人参）对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，正如圣约翰草和大蒜所显示的那样。药物相互作用可能增加抗逆转录病毒浓度，使患者面临毒性风险，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都主要依靠细胞色素P450 (CYP) 3A4代谢来消除它们。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。

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).