Joshi Deepa, Jamadarkhana Prashant, Kumbhare Suchit, Singh Amarinder, Kotecha Jignesh, Bunger Deepak, Shiwalkar Ajay, Mohanan Anookh, Dutt Chaitanya
Torrent Pharmaceuticals Ltd., Ahmedabad, India.
Front Pharmacol. 2021 Sep 17;12:729424. doi: 10.3389/fphar.2021.729424. eCollection 2021.
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 = 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 (C), area under the plasma concentration (AUC), time to C (T), 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. C was more than the dose-proportional for all doses in all cohorts. T 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%, = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, = 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. EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD).
TRC150094是一种新型线粒体调节剂，在临床前研究中，它可以通过改善胰岛素抵抗来恢复代谢灵活性。本研究的主要目的是在46名超重/肥胖的成年和老年受试者中开展两项双盲、随机、I期研究（单次递增剂量研究和多次递增剂量研究）后，评估口服TRC150094的安全性、耐受性和药代动力学（PK）。此外，还评估了TRC150094对药效学（PD）疗效标志物的影响。在预先设定的时间点进行PK评估，包括最大浓度（Cmax）、血浆浓度-时间曲线下面积（AUC）、达峰时间（Tmax）和消除半衰期（t1/2）。PD评估包括载脂蛋白B（ApoB）、甘油三酯、通过磁共振波谱（MRS）测定的肝脏脂肪以及心肺运动试验（CPET）参数。TRC150094吸收迅速，在非老年和老年队列中，TRC150094的AUC在所有剂量下均呈剂量依赖性增加。所有队列中所有剂量的Cmax均超过剂量比例。Tmax范围为0.25至4小时，t1/2范围为15至18小时，这使得TRC150094适合每日一次给药。食物不影响药物的整体吸收。TRC150094的代谢产物为葡萄糖醛酸和硫酸盐结合物，20%的药物以原形经尿液排泄。50mg的TRC150094使甘油三酯呈改善趋势。50mg剂量后观察到Apo B显著降低（-2.34%对13.24%，P = 0.008），然而，150mg剂量后并非如此（8.78%对13.24%，P = 0.1221）。其他参数，如肝脏脂肪和胰岛素敏感性指数（HOMA-IR、源自口服葡萄糖耐量试验的松田指数）在50mg剂量时呈改善趋势。在安全性方面，报告的所有不良事件严重程度均为轻度至中度。没有不良事件被认为肯定或可能与治疗相关，也没有异常的实验室检查结果。总之，TRC150094的PK呈线性，食物对其无临床显著影响。TRC150094及其代谢产物提示药物相互作用的可能性较小。总体而言，TRC150094确保了安全性，并对所有受试者均显示出适用性。欧盟临床试验编号：2009-014941-10（单次递增剂量研究），印度临床试验注册编号：CTRI/2009/091/000601（多次递增剂量研究）。
