Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA.
Chimerix, Inc., 2505 Meridian Pkwy, STE 340, Durham, NC 27713, USA.
Antiviral Res. 2015 May;117:115-21. doi: 10.1016/j.antiviral.2015.02.007. Epub 2015 Mar 4.
Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox.
布昔洛韦（BCV）对包括天花在内的双链 DNA 病毒具有广泛的体外活性，目前正在开发用于治疗天花以及其他双链 DNA 病毒感染的药物。BCV 此前已在多种天花动物模型中表现出活性。在这里，我们报告了一项随机、双盲、安慰剂对照研究的结果，该研究评估了新型“人源化”BCV 方案治疗新西兰白兔感染高度致死性兔痘病毒的疗效和药代动力学，兔痘病毒是一种特征明确的天花模型。与安慰剂相比，所有 BCV 治疗组的存活率均呈剂量依赖性增加。测定了兔外周血单核细胞（PBMC）中cidofovir 二磷酸（CDV-PP），即活性抗病毒药物的浓度，与提议用于治疗天花的剂量在人类中产生的浓度进行比较。给予 BCV 的兔子的 PBMC 中 CDV-PP 的暴露量与提议用于治疗天花的剂量所产生的人类暴露量相匹配，该剂量目前也正在评估其他适应症。这项研究的结果表明，BCV 在天花的兔痘模型中具有活性，并且可以将在该模型中有效剂量的药物按比例扩大到提议用于治疗天花的人类剂量和方案。
