The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long‐Chain Fatty Acid Oxidation Disorders

Abstract

Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.

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

“…At the same body weight‐adjusted dose level, the exposure of heptanoate in pediatric patients is expected to be similar to that in adults. This simulation result was consistent with the observed PK data reported previously 11 . Once body weight was allometrically scaled with CL/F and V/F, body mass index did not affect these parameters.…”

“…This result suggests that an extrahepatic metabolism plays a significant role in the overall metabolic elimination of heptanoate. This result is consistent with the proposed major elimination pathway via beta‐oxidation occurring in most tissues and organs containing mitochondria 10,11 . The estimated CL/F in patients with LC‐FAOD is ∼19% lower than that in healthy subjects, but the difference appears to be minor considering the observed BSV and clinically insignificant.…”

“…This result is consistent with the proposed major elimination pathway via beta-oxidation occurring in most tissues and organs containing mitochondria. 10,11 The estimated CL/F in patients with LC-FAOD is ∼19% lower than that in healthy subjects, but the difference appears to be minor considering the observed BSV and clinically insignificant. The model-estimated elimination T 1/2 in patients with LC-FAOD was ∼1.7 hours, supporting the proposed dosing frequency (four times or more per day).…”

“…The quantitation of heptanoate in human plasma was conducted by validated liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) methods. Details of the bioanalytical assays were reported previously 11 . The descriptions of clinical studies, dose regimen, PK sampling schedule, and number of subjects are presented in Table S1.…”

“…The pharmacokinetics (PK) of triheptanoin and its metabolites in humans following oral administrations were investigated using the available PK data from two clinical studies and reported previously. 11 Briefly, the systemic exposure of triheptanoin following oral administration was negligible as triheptanoin is hydrolyzed to glycerol and heptanoate before it is absorbed from the GI tract. Heptanoate can be metabolized to four‐ and five‐carbon ketone bodies (ie, beta‐hydroxybutyrate [BHB] and beta‐hydroxypentoate [BHP]) in the liver and circulated via the bloodstream.…”