Ultragenyx Pharmaceutical Inc., Novato, California, USA.
Certara Strategic Consulting, Princeton, New Jersey, USA.
Clin Pharmacol Drug Dev. 2022 Nov;11(11):1264-1272. doi: 10.1002/cpdd.1145. Epub 2022 Jul 31.
Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC-FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first-order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one-compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC-FAOD. The typical CL/F in adult subjects with LC-FAOD was ≈19% lower than that in healthy subjects. Model-estimated elimination half-life for LC-FAOD patients was ∼1.7 hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.
三庚酸甘油酯是一种奇数碳、中链甘油三酯，由三个脂肪酸组成，每个脂肪酸有七个碳原子连接在甘油骨架上，用于治疗长链脂肪酸氧化障碍（LC-FAOD）的成人和儿科患者。共纳入了 13 名健康成年受试者和 30 名 LC-FAOD 成年和儿科受试者的 562 个血浆庚酸酯（三庚酸甘油酯最丰富和药理学上活跃的代谢物）浓度，用于群体药代动力学（PK）分析。在几个受试者中观察到的庚酸酯的多个峰特征是双一级吸收，第二吸收隔室有滞后时间。庚酸酯在人血浆中的处置通过一室分布和线性消除得到很好的描述。表观清除率（CL/F）和表观分布容积按比例与体重进行了体表面积校正，以描述 LC-FAOD 受试者在广泛年龄范围内的 PK 数据。LC-FAOD 成年受试者的典型 CL/F 约比健康受试者低 19%。模型估计 LC-FAOD 患者的消除半衰期约为 1.7 小时，支持推荐每天给药≥4 次的给药频率。协变量分析表明，年龄、种族和性别不会导致庚酸酯暴露的临床有意义变化。
