Rare Brain Disorders Program, Department of Neurology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. Mail Code 8813, Dallas, TX, 75390, USA.
Department of Pharmacy Practice and Clinical Pharmacology, Experimental Therapeutics Center, Texas Tech University Health Sciences Center, Dallas, TX, 75235, USA.
Sci Rep. 2023 Mar 1;13(1):3465. doi: 10.1038/s41598-023-30578-z.
Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4-6, 6.8-10 and 11-16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, β-ketopentanoate and β-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential.ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017.
三庚酸甘油酯（Triheptanoin）是一种 7 碳庚酸的三酸甘油酯，可通过直接氧化或 5 碳酮体生成进行补氮作用（anaplerosis），或补充中间代谢转换过程中丢失的碳。在这种情况下，三庚酸甘油酯可用于治疗葡萄糖转运蛋白 1 缺乏性脑病（G1D）。1g/Kg/天的口服三庚酸甘油酯剂量接近总热量摄入的 35%，可改善 G1D 的癫痫发作和认知功能。这为确定最大、可能更高的剂量提供了动力。我们采用了在肿瘤学中有用的 3+3 剂量发现方法，研究了三个年龄组：4-6 岁、6.8-10 岁和 11-16 岁。这使我们能够为每个年龄组确定可耐受的最大剂量为每天卡路里摄入量的 45%。通过分析血液指标来确定安全性。在中年组中，有 1 例 6 例患者出现了 1 例剂量限制毒性，这与所有组的胃肠道耐受性经常降低有关。在另一组 G1D 患者中测定了三庚酸甘油酯后的血酮。在这些患者中，β-酮戊酸和β-羟戊酸的浓度显著增加，但存在差异。这些结果为三庚酸甘油酯在 G1D 中的严格临床研究提供了剂量和初步耐受性、安全性和生酮潜力。
ClinicalTrials.gov 注册号：NCT03041363，首次注册日期 2017 年 2 月 2 日。
