AbbVie, North Chicago, Illinois, United States of America.
Pfizer, Chicago, Illinois, United States of America.
PLoS Negl Trop Dis. 2023 Jul 10;17(7):e0011392. doi: 10.1371/journal.pntd.0011392. eCollection 2023 Jul.
The parasitic filariae responsible for onchocerciasis and lymphatic filariasis are host to an endosymbiotic bacterium, Wolbachia, which is essential to the fertility and development of the parasites. We performed a Phase-I pharmacokinetic, safety and food-effect study on single and multiple ascending doses of flubentylosin (ABBV-4083), a macrolide antibacterial with activity against Wolbachia, intended to sterilize and eliminate the parasites.
Seventy-eight healthy adults were exposed to flubentylosin; 36 were exposed to single ascending 40, 100, 200, 400 or 1000 mg doses; 12 received 1000 mg in the food-effect part; and 30 received multiple ascending daily doses of 100 mg for 7 days, 200 mg for 7 or 14 days, or 400 mg for 7 or 14 days. Twenty-two subjects received placebo.
Maximum concentrations (Cmax) of flubentylosin were reached after 1-2 hours, with a half-life < 4 hours at doses ≤ 400 mg. Cmax and AUC increased in a more than dose-proportional manner, with similar exposure after multiple dose administration. The most frequently reported adverse events were nausea (8/78, 10%) and headache (6/78, 8%). Two subjects given a single dose of flubentylosin 1000 mg in the food-effect part experienced reversible asymptomatic ALT and AST elevations at Grade 2 or Grade 4, with no elevation in bilirubin, deemed related to study drug. The effect of food on exposure parameters was minimal. No treatment-related serious adverse events were reported.
Flubentylosin 400 mg for 14 days was the maximum tolerated dose in this first-in-human, Phase-I study in healthy adults. Based on preclinical pharmacokinetic/pharmacodynamic modeling, flubentylosin 400 mg once daily for 7 or 14 days is expected to be an effective dose. A Phase-II, proof-of-concept study with flubentylosin using these regimens is currently ongoing in patients with onchocerciasis in Africa.
引起盘尾丝虫病和象皮病的寄生丝虫是内共生菌沃尔巴克氏体的宿主，这种内共生菌对寄生虫的生殖和发育至关重要。我们对 flubentylosin（ABBV-4083）进行了 I 期药代动力学、安全性和食物影响研究，这是一种具有抗沃尔巴克氏体活性的大环内酯类抗菌药物，旨在使寄生虫绝育和消除。
78 名健康成年人接受了 flubentylosin 暴露；36 人接受了单次递增 40、100、200、400 或 1000mg 剂量；12 人在食物影响部分接受了 1000mg；30 人接受了每日递增剂量 100mg 连续 7 天、200mg 连续 7 天或 14 天、400mg 连续 7 天或 14 天。22 名受试者接受了安慰剂。
flubentylosin 的最大浓度（Cmax）在 1-2 小时内达到，在剂量≤400mg 时半衰期<4 小时。Cmax 和 AUC 呈剂量比例以上增加，多次给药后暴露相似。最常报告的不良事件是恶心（78 例中的 8 例，10%）和头痛（78 例中的 6 例，8%）。在食物影响部分接受 1000mg flubentylosin 单次剂量的 2 名受试者出现可逆的无症状 ALT 和 AST 升高，达到 2 级或 4 级，胆红素无升高，被认为与研究药物有关。食物对暴露参数的影响很小。没有报告与治疗相关的严重不良事件。
在这项在健康成年人中进行的首次 I 期人体研究中，flubentylosin 400mg 连续 14 天是最大耐受剂量。基于临床前药代动力学/药效学模型，flubentylosin 400mg 每天一次连续 7 天或 14 天有望成为一种有效剂量。目前正在非洲患有盘尾丝虫病的患者中进行使用这些方案的 flubentylosin Ⅱ期概念验证研究。
