Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 10⁵ plaque-forming units (PFU; 90% lethal dose [LD₉₀]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID–1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID–1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [C_max]) and the time of the last quantifiable concentration (AUC_last) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.

中文翻译：

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一种潜在的天花治疗药物布林西多福韦在致死性猴痘病毒动物模型中的药代动力学和疗效

由天花病毒(VARV) 引起的天花于 1980 年被根除；然而，天花病毒的生物恐怖威胁仍然存在，需要现成的治疗方法。当前的准备活动认识到口服抗病毒药物的重要性，并推荐具有不同作用机制的治疗方法。猴痘病毒（MPXV）与天花病毒密切相关，引起高度相似的临床人类疾病，可作为天花抗病毒检测的替代品。草原犬鼠 MPXV 模型已被表征并用于研究抗痘病毒疗法的功效，包括最近批准的 TPOXX (tecovirimat)。Brincidofovir (BCV; CMX001) 已显示出对双链 DNA 病毒（包括痘病毒）的抗病毒活性。为了确定向草原犬鼠口服给药后 BCV 的暴露量，进行了药代动力学 (PK) 研究。对 BCV 血浆浓度的分析表明存在变异性，这可能是由于动物的近亲繁殖性质所致。为了确定 MPXV 土拨鼠模型中的 BCV 功效，用 9 × 10 ^{5对动物组进行鼻内攻击}MPXV 在接种第 0 天 (ID0) 的噬斑形成单位 (PFU；90% 致死剂量 [LD ₉₀ ])。根据 BCV 治疗的第一天相对于接种日（ID-1、ID0 或 ID1）将动物分组。注意到疗效的趋势取决于治疗的开始（ID-1 为 57%，ID0 为 43%，ID1 为 29%），但低于其他动物模型中的表现。PK 数据分析表明，BCV 血浆暴露（最大浓度 [ _Cmax ]）和最后一次可量化浓度的时间（AUC _last）低于给予相同剂量的其他动物模型，表明次优 BCV 暴露可以解释对生存的保护作用较低。