Food Effect on the Pharmacokinetics of VC004, a Tropomyosin Receptor Kinase Inhibitor: A Randomized Crossover Trial in Healthy Chinese Subjects

IF 2.9 3区医学 Q2 PHARMACOLOGY & PHARMACY Clinical Drug Investigation Pub Date : 2023-12-19 DOI:10.1007/s40261-023-01334-y

Linlin Hu, Qiuyue Sun, Lu Tang, Mingmin Cai, Wei Qian, Ting Dou, Huiping Wang, Yong Wu, Yongqiang Liu

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Abstract

Background and Objective

VC004 is a novel next-generation tropomyosin receptor kinase (TRK) inhibitor that is approved for the treatment of advanced or metastatic NTRK fusion-positive solid tumors and abrogated the drug resistance of the first-generation TRK inhibitors. The objective of the present study was to evaluate the effect of food on the pharmacokinetics and safety of VC004.

Methods

The study was a randomized, open-label, two-period crossover, single-dose, phase I clinical trial. A total of 16 healthy subjects participated the trial. Subjects fasted for 10 h before drug administration in both fasting and fed states. Subjects received VC004 50 mg orally in the fasting state and after a high caloric food in the fed state. Blood samples at the designated time points were collected to determine the plasma concentration of VC004. Safety evaluation in both the fasted and fed periods were assessed via vital sign monitoring and clinical laboratory tests.

Results

The maximum plasma concentration (C_max) of VC004 in fed group decreased by 32.8%, corresponding with the slower absorption rate (time to C_max (T_max) delayed by almost 3 h) compared with the fasting group. Ratios of geometric means (GMRs) and 90% confidence intervals (90% CIs) of C_max, the area under the curve of plasma concentration-time from zero to the last measurable concentration (AUC_0–t), and AUC from zero to infinity (AUC_0–∞) for VC004 between the two states were 67.18 (58.16–77.60), 103.59 (95.04–112.92) and 103.55 (95.63–112.11), respectively. No serious adverse events (AEs) occurred; only three grade 1 or grade 2 adverse events occurred in the fasted group, who recovered by the end of the study.

Conclusions

The intake of high calorie food decreased the absorption rate and increased the T_max of VC004, while the AUC values were similar in both groups. No serious adverse event was reported. In conclusion, food does not alter the pharmacokinetics and safety profile of VC004 in a clinically meaningful manner.

Trial Registration

ClinicalTrials.gov ID: NCT055528120.

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食物对肌球蛋白受体激酶抑制剂 VC004 药物代谢动力学的影响：中国健康受试者的随机交叉试验

背景和目的VC004是一种新型的新一代肌球蛋白受体激酶（TRK）抑制剂，已被批准用于治疗晚期或转移性NTRK融合阳性实体瘤，并能消除第一代TRK抑制剂的耐药性。本研究旨在评估食物对 VC004 药代动力学和安全性的影响。方法本研究是一项随机、开放标签、两期交叉、单剂量的 I 期临床试验。共有 16 名健康受试者参加了试验。受试者在空腹和进食状态下服药前均禁食 10 小时。受试者在空腹状态下口服 VC004 50 毫克，在进食状态下进食高热量食物后口服 VC004 50 毫克。在指定时间点采集血样以测定 VC004 的血浆浓度。结果与空腹组相比，进食组 VC004 的最大血浆浓度（Cmax）降低了 32.8%，这与较慢的吸收率有关（达到 Cmax 的时间（Tmax）延迟了近 3 小时）。两种状态下 VC004 的 Cmax、血浆浓度-时间曲线下面积（从零到最后可测量浓度）（AUC0-t）和 AUC（从零到无穷大）（AUC0-∞）的几何平均比（GMR）和 90% 置信区间（90% CI）分别为 67.18（58.16-77.60）、103.59（95.04-112.92）和 103.55（95.63-112.11）。结论摄入高热量食物降低了 VC004 的吸收率，增加了其 Tmax，但两组的 AUC 值相似。没有严重不良事件的报告。总之，食物不会以有临床意义的方式改变VC004的药代动力学和安全性：NCT055528120.

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来源期刊

Clinical Drug Investigation 医学-药学

CiteScore

5.90

自引率

3.10%

发文量

108

审稿时长

6-12 weeks

期刊介绍： Clinical Drug Investigation provides rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. The Journal includes: -Clinical trials, outcomes research, clinical pharmacoeconomic studies and pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs. -Clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice. -Pharmacodynamic and pharmacokinetic studies in healthy volunteers in which significant implications for clinical prescribing are discussed. -Studies focusing on the application of drug delivery technology in healthcare. -Short communications and case study reports that meet the above criteria will also be considered. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in Clinical Drug Investigation may be accompanied by plain language summaries to assist readers who have some knowledge, but non in-depth expertise in, the area to understand important medical advances.