PDF(Pubmed)
Abstract：
Fosmanogepix [FMGX, APX001; active form: manogepix (MGX), APX001A] is a first-in-class, intravenous (IV)/oral antifungal currently being evaluated for invasive fungal disease treatment. Data from two phase 1, placebo-controlled studies [IV-oral switch (study 1) and multiple IV doses (study 2)] evaluating FMGX tolerability, and pharmacokinetics (PK) are presented. Healthy adults (study 1: 18-65 years; study 2: 18-55 years) were eligible (randomized 3:1 to FMGX: placebo). Eleven participants completed study 1. In study 2, 51 participants (48 planned + 3 replacement) were enrolled in six cohorts (8 participants each; 34 completed the study). In study 1, overall MGX systemic exposures were comparable from day 1 to day 42 of dosing; steady-state plasma concentrations were achieved in ≤24 h following two IV loading doses (1,000 mg) and exposures maintained after switching [IV (600 mg) to daily oral doses (800 mg)]. FMGX was safe and well-tolerated. In study 2, FMGX IV doses (loading doses twice daily/maintenance doses once daily; 3-h infusion) of 1,500/900 mg (cohort A), 900/900 mg (cohort B), and 1,000/900 mg (cohort C: with ondansetron) were not well-tolerated; most participants reported nausea and infrequent vomiting. FMGX IV doses of 1,000/750 mg (cohort D), 1,000/850 mg (cohort E), and 1,000/900 mg (cohort F: ondansetron prn) were relatively better tolerated. Steady-state systemic exposures were achieved between days 2 and 4. All cohorts had similar geometric mean (GM) concentrations during maintenance dosing and similar GM PK parameters. Dosing regimen evaluated in study 1 was safe, well-tolerated, and may be used for future clinical evaluations.
摘要：
Fosmanogepix[FMGX，APX001；活性形式：manogepix（MGX），APX001A]是一流的，目前正在评估用于侵袭性真菌病治疗的静脉（IV）/口服抗真菌药物。来自两个1期安慰剂对照研究[IV-口服转换（研究1）和多个IV剂量（研究2）]的数据评估FMGX耐受性，和药代动力学（PK）。健康成年人（研究1：18-65岁；研究2：18-55岁）符合条件（随机3：1至FMGX：安慰剂）。11名参与者完成了研究1。在研究2中，51名参与者(48名计划+3名替代)被纳入6个队列(每个8名参与者;34名完成研究)。在研究1中，从给药的第1天到第42天，总体MGX全身暴露是可比的；在两次IV负荷剂量（1,000mg）后≤24小时内达到稳态血浆浓度，并在切换[IV（600mg）至每日口服剂量（800mg）]后维持暴露。FMGX是安全且耐受性良好的。在研究2中，FMGXIV剂量（每天两次负荷剂量/每天一次维持剂量；3小时输注）为1,500/900mg（队列A），900/900毫克（队列B），1,000/900mg(队列C:使用昂丹司琼)耐受性不佳;大多数参与者报告有恶心和不频繁的呕吐.FMGXIV剂量为1,000/750mg（队列D），1,000/850毫克（队列E），1,000/900mg（队列F：昂丹司琼prn）的耐受性相对较好。在第2天和第4天之间实现稳态系统暴露。所有队列在维持给药期间具有相似的几何平均(GM)浓度和相似的GMPK参数。研究1中评估的给药方案是安全的，耐受性良好,并可用于未来的临床评估。
