TRC150094,一种新型的线粒体调节剂,可以通过改善临床前研究中的胰岛素抵抗来恢复代谢灵活性。这项研究的主要目的是评估安全性,耐受性,口服TRC150094进行两次双盲后的药代动力学(PK),随机化,第一阶段研究,单次递增剂量(SAD)和多次递增剂量(MAD),n=46,在超重/肥胖的成年人和老年人中。此外,评估TRC150094对药效学(PD)功效标志物的影响.PK评估,包括最大浓度(Cmax),血浆浓度下面积(AUC),时间Cmax(Tmax),和消除半衰期(t½),在预先指定的时间点进行评估。PD评估包括载脂蛋白B(ApoB),甘油三酯,磁共振波谱(MRS)和心肺运动试验(CPET)参数的肝脏脂肪。TRC150094被迅速吸收,TRC150094的AUC在非老年和老年队列的所有剂量中以剂量依赖性方式增加。在所有队列中,Cmax大于所有剂量的剂量比例。Tmax范围从0.25到4小时,t½的范围从15到18小时,使TRC150094适合每日一次给药。食物不会干扰药物的整体吸收。TRC150094的代谢产物是葡萄糖醛酸和硫酸盐的结合物,20%的药物在尿液中排泄不变。50mg的TRC150094显示出甘油三酯的改善趋势。50mg剂量后观察到ApoB显着降低(-2.34vs.13.24%,p=0.008),那是,然而,150毫克后情况并非如此(8.78vs.13.24%,p=0.1221)。其他参数,如肝脂肪和胰岛素敏感性指数(HOMA-IR,来自OGTT的MATSUDA指数)显示出50mg剂量的改善趋势。在安全方面,报告的所有AE的严重程度均为轻度至中度.没有任何不良事件被认为与治疗明确或可能相关,并且没有异常的实验室发现。总之,TRC150094的PK是线性的,没有临床上显著的食物效应。TRC150094及其代谢物表明药物-药物相互作用的可能性较小。总的来说,TRC150094确保所有受试者的安全性和适用性。临床试验注册:EUDRACT:2009-014941-10(SAD)和CTR-印度注册:CTRI/2009/091/000601(MAD)。
TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of
TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters.
TRC150094 was rapidly absorbed, and the AUC of
TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine.
TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (-2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect.
TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall,
TRC150094 ensured safety and exhibited suitability for all subjects. Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD).