Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long‐Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin

Abstract

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.