Triheptanoin, sold under the brand name Dojolvi, is a medication for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). The most common adverse reactions include abdominal pain, diarrhea, vomiting, and nausea. Triheptanoin was approved for medical use in the United States in June 2020. Triheptanoin is a

triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...

that is composed of three seven-carbon (C7:0)

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

s. These odd-carbon fatty acids are able to provide anaplerotic substrates for the

TCA cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...

. Triheptanoin is used clinically in humans to treat inherited metabolic diseases, such as

pyruvate carboxylase Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme () of the ligase class that catalyzes (depending on the species) the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA). Image:Pyruvic-acid-2D-sk ...

deficiency and

carnitine palmitoyltransferase II deficiency Carnitine palmitoyltransferase II deficiency is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization ...

. It also appears to increase the efficacy of the

ketogenic diet The ketogenic diet is a high- fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than ca ...

as a treatment for epilepsy. Since triheptanoin is composed of odd-carbon fatty acids, it can produce

ketone bodies Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...

with five carbon atoms, as opposed to even-carbon fatty acids which are metabolized to ketone bodies with four carbon atoms. The five-carbon ketones produced from triheptanoin are

beta-ketopentanoate 3-Oxopentanoic acid, or ''beta''-ketopentanoate, is a 5-carbon ketone body. It is made from odd carbon fatty acids in the liver and rapidly enters the brain. As opposed to 4-carbon ketone bodies, ''beta''-ketopentanoate is anaplerotic, meanin ...

and

beta-hydroxypentanoate 3-Hydroxypentanoic acid, or beta-hydroxypentanoate, is the organic compound with the formula . It is one of the hydroxypentanoic acids. It is made from odd carbon fatty acids in the liver and rapidly enters the brain. As opposed to 4-carbon ke ...

. Each of these ketone bodies easily crosses the blood–brain barrier and enters the brain.

Medical uses

Dojolvi is indicated as a source of calories and fatty acids for the treatment of children and adults with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).

History

Triheptanoin was designated an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in 2006, 2008, 2014, and 2015. Triheptanoin was also designated an orphan drug by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA). Triheptanoin was approved for medical use in the United States in June 2020. The FDA approved triheptanoin based on evidence from three clinical trials (Trial 1/NCT018863, Trial 2/NCT022141 and Trial 3/NCT01379625). The trials enrolled children and adults with LC-FAOD. Trials 1 and 2 were conducted at 11 sites in the United States and the United Kingdom, and Trial 3 was conducted at two sites in the United States. Trial 1 and Trial 2 were used to evaluate the side effects of triheptanoin. Both trials enrolled children and adults diagnosed with LC-FAOD. In Trial 1, participants received triheptanoin for 78 weeks. Trial 2 enrolled participants from other trials who were already treated with triheptanoin (including those from Trial 1) as well as participants who were never treated with triheptanoin before. Trial 2 is still ongoing and is planned to last up to five years. The benefit of triheptanoin was evaluated in Trial 3 which enrolled children and adults with LC-FAOD. Half of the participants received triheptanoin and half received trioctanoin for four months. Neither the participants nor the investigators knew which treatment was given until the end of the trial. The benefit of triheptanoin in comparison to trioctanoin was assessed by measuring the changes in heart and muscle function.

Medical uses

History

Names

References

Further reading

External links