Department of Clinical Pharmacology, QPS-Netherlands, Groningen, The Netherlands.
General Clinical Research Center, Taipei Veterans General Hospital, Taipei, Taiwan.
Clin Drug Investig. 2021 Jan;41(1):65-76. doi: 10.1007/s40261-020-00981-9. Epub 2020 Dec 17.
Matrix metalloproteinases (MMPs) are proteases with different biological and pathological activities, and many have been linked to several diseases. Targeting individual MMPs may offer a safer therapeutic potential for several diseases. We assessed the safety, tolerability, and pharmacokinetics of FP-025, a novel, highly selective oral matrix metalloproteinase-12 inhibitor, in healthy subjects.
Two randomized, double-blind, placebo-controlled studies were conducted. Study I was a first-in-man study, evaluating eight single ascending doses (SADs) (50-800 mg) in two formulations: i.e., neat FP-025 in capsule (API-in-Capsule) and in an amorphous solid dispersion (ASD-in-Capsule) formulation. In Study II, three multiple ascending doses (MADs) (100, 200, and 400 mg, twice daily) of FP-025 (ASD-in-Capsule) were administered for 8 days, including a food-effect evaluation.
Ninety-six subjects were dosed. Both formulations were well tolerated with one adverse event (AE) reported in the 800 mg API-in-Capsule SAD group and seven AEs throughout the MAD groups. The exposure to FP-025 was low with the API-in-Capsule formulation; it increased dose-dependently with the ASD-in-Capsule formulation, with which exposure to FP-025 increased in a greater-than-dose-proportional manner at lower doses (≤ 100 mg) but less proportionally at higher doses. The elimination half-life (t) was between 6 (Study I) and 8 h (Study II). Accumulation of FP-025 was approximately 1.7-fold in the MAD study. Food intake delayed the rate of absorption, but without effect in the extent of absorption or bioavailability.
FP-025 was well tolerated and showed a favorable pharmacokinetic profile following ASD-in-Capsule dosing. Efficacy studies in target patient populations, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, are warranted.
www.clinicaltrials.gov : NCT02238834 (Study I); NCT03304964 (Study II). Trial registration date: Study I was registered on 12 September 2014 while study II was registered on 9 October 2017.
基质金属蛋白酶（MMPs）是具有不同生物学和病理学活性的蛋白酶，其中许多与多种疾病有关。针对特定的 MMP 可能为多种疾病提供更安全的治疗潜力。我们评估了新型高度选择性口服基质金属蛋白酶-12 抑制剂 FP-025 在健康受试者中的安全性、耐受性和药代动力学。
进行了两项随机、双盲、安慰剂对照研究。研究 I 是首次人体研究，评估了两种制剂的 8 个单递增剂量（SAD）（50-800mg）：即胶囊中的 neat FP-025（API-in-Capsule）和无定形固体分散体（ASD-in-Capsule）制剂。在研究 II 中，FP-025（ASD-in-Capsule）的三个递增剂量（MAD）（100、200 和 400mg，每日两次）给药 8 天，包括食物效应评估。
共 96 名受试者接受了治疗。两种制剂均具有良好的耐受性，API-in-Capsule 800mg SAD 组报告了 1 例不良事件（AE），MAD 组报告了 7 例 AE。API-in-Capsule 制剂的 FP-025 暴露量较低；随着 ASD-in-Capsule 制剂的使用，暴露量呈剂量依赖性增加，其中在较低剂量（≤100mg）时，FP-025 的暴露量呈超剂量比例增加，但在较高剂量时则呈比例增加。MAD 研究中 FP-025 的消除半衰期（t）为 6（研究 I）至 8 小时（研究 II）。在 MAD 研究中，FP-025 的蓄积约为 1.7 倍。食物摄入延迟了吸收速度，但对吸收程度或生物利用度没有影响。
FP-025 经 ASD-in-Capsule 给药后耐受性良好，药代动力学特征良好。需要在哮喘、慢性阻塞性肺疾病（COPD）和肺纤维化等目标患者人群中进行疗效研究。
www.clinicaltrials.gov：NCT02238834（研究 I）；NCT03304964（研究 II）。试验注册日期：研究 I 于 2014 年 9 月 12 日注册，而研究 II 于 2017 年 10 月 9 日注册。
