Researchers were able to determine the pharmacokinetic characteristics of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, in healthy people and patients with long chain fatty acid oxidation disorder (LCFAOD) using a nonlinear mixed effects model.
The model could accurately estimate the elimination half-life of triheptanoin in patients with LCFAOD and be used to calculate the best dosing frequency of triheptanoin for the treatment of patients.
Triheptanoin, marketed under the brand name Dojolvi® by Ultragenyx Pharmaceutical Inc., in Novato, California, is used as a source of calories in adults and children with LCFAOD.
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Here, a team led by Wendy Putnam, PhD, from Ultragenyx conducted a population pharmacokinetic analysis on 13 healthy volunteers and 30 patients with LCFAOD.
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They found that the typical apparent clearance of triheptanoin in adults with LCFAOD was around 19% lower than in healthy people. Its elimination half-life as estimated by the model was about 1.7 hours in patients. This, the researchers said, supports a recommended dosing frequency of at least 4 times a day.
They also calculated that “age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate”.
These findings are published in the journal Clinical Pharmacology in Drug Development.
Triheptanoin is an odd-carbon, medium-chain triglyceride with 3 fatty acids including odd carbons attached to a glycerol backbone. Because patients with LCFAOD cannot metabolize long chain fatty acids, their diet is supplemented with medium chain fatty acids like triheptanoin as a source of energy.
The body hydrolyzes triheptanoin into glycerol and heptanoate using pancreatic lipases in the gastrointestinal tract. Heptanoate is absorbed here and then distributed to the body via the bloodstream. Once inside the mitochondria it is metabolized to acetyl-CoA and propionyl-CoA by the short and medium chain fatty acid oxidation enzymes bypassing the carnitine shuttle and long chain fatty acid oxidation enzymes that are deficient in patients with LCFAOD.
Reference
Lee SK, Gosselin NH, Jomphe C, McKeever K, Putnam W. Population pharmacokinetics of heptanoate in healthy subjects and patients with long-chain fatty acid oxidation disorders treated with triheptanoin. Clin Pharmacol Drug Dev. Published online July 31, 2022. doi:10.1002/cpdd.1145
