在体外评估乙型肝炎和丁型肝炎病毒进入抑制剂myrcludex B的药

StephenW

Antivir Ther. 2017 Nov 14. doi: 10.3851/IMP3206. [Epub ahead of print]
Drug-drug interaction potential of the hepatitis B and hepatitis D virus entry inhibitor myrcludex B assessed in vitro.Blank A1,2, Meier K1,2, Urban S2,3, Haefeli WE1,2, Weiss J1,2.
Author information
1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.2German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany.3Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.

AbstractBACKGROUND: Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be co-administered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro.
METHODS: Inhibition of P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates. Inhibition of cytochrome P450 enzymes (CYPs) was assessed with commercially available kits. mRNA induction of drug transporting and metabolizing enzymes was measured in LS180 cells after four days of treatment by quantitative real-time PCR. PXR activation was assessed using a reporter-gene assay.
RESULTS: Whereas activities of P-gp and BCRP were not influenced by myrcludex B, OATP1B1 and OATP1B3 were specifically inhibited with an IC50 of 0.5 and 8.7 µM, respectively. Myrcludex B weakly inhibited all CYPs tested at concentrations ≥ 10 µM except CYP2D6, which was not inhibited at concentrations up to 2 µM. Myrcludex B had no influence on mRNA expression of CYP1A1, CYP3A4, UGT1A3, ABCB1, ABCC2, and ABCG2 and on PXR activity.
CONCLUSIONS: Our in vitro study suggests that myrcludex B does not have a major risk to act as a perpetrator drug. A potential inhibition of the uptake transporters OATP1B1 and OATP1B3 and a previous clinical finding of a potential CYP3A inhibition, requires further evaluation and should be carefully addressed in future trials.


PMID:29134945DOI:10.3851/IMP3206

StephenW

Antivir Ther。 2017年11月14日doi：10.3851 / IMP3206。 [电子版提前打印]
在体外评估乙型肝炎和丁型肝炎病毒进入抑制剂myrcludex B的药物 - 药物相互作用潜力。
空白A1,2，Meier K1,2，城市S2,3，Haefeli WE1,2，Weiss J1,2。
作者信息

1
    德国海德堡海德堡大学临床药理学和药物流行病学系。
2
    德国海德堡中心感染研究中心（DZIF），海德堡合作伙伴网站。
3
    德国海德堡海德堡大学医院感染性疾病分子病毒学系。

抽象
背景：

Myrcludex B是慢性乙型肝炎或B / D感染患者的一流病毒进入抑制剂。在患者中，将与该疾病或合并症所需的药物共同施用。我们旨在通过表征myrcludex B对体外相关药物转运和代谢酶的影响来确定药物相互作用的风险。
方法：

在过表达各自的细胞中测量对P-糖蛋白（P-gp，ABCB1），乳腺癌耐受蛋白（BCRP / ABCG2）和有机阴离子转运多肽1B1和1B3（OATP1B1 / SLCO1B1和OATP1B3 / SLCO1B3）使用荧光底物的转运蛋白。用市售试剂盒评估细胞色素P450酶（CYP）的抑制。在定量实时PCR处理四天后，在LS180细胞中测量药物转运和代谢酶的mRNA诱导。使用报道基因测定评估PXR活化。
结果：

而P-gp和BCRP的活性不受myrcludex B的影响，OATP1B1和OATP1B3被特异性抑制，IC50分别为0.5和8.7μM。 Myrcludex B弱抑制浓度≥10μM的所有CYPs，CYP2D6除外，浓度高达2μM时不受抑制。 Myrcludex B对CYP1A1，CYP3A4，UGT1A3，ABCB1，ABCC2和ABCG2 mRNA表达和PXR活性无影响。
结论：

我们的体外研究表明，myrcludex B没有作为行为人药物的主要风险。摄取转运蛋白OATP1B1和OATP1B3的潜在抑制以及先前的潜在CYP3A抑制的临床发现需要进一步的评估，并且应在将来的试验中仔细解决。

结论：
    29134945
DOI：
    10.3851 / IMP3206