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DOJOLVI (triheptanoin) for LC-FAOD

In February 2021, Health Canada approved DOJOLVI, or triheptanoin, the first drug indicated for pediatric and adult patients with long-chain fatty acid oxidation disorders (LC-FAOD).

How triheptanoin differs from trioctanoin

Current treatment for LC-FAOD includes supplementation with MCTs (medium-chain triglycerides). Traditionally, commercially available MCT was composed of a mix of even-chain fatty acids: C8, C10, and some C12. It was assumed that that type of MCT would bypass the energy deficiencies present in patients with LC-FAOD. However, clinical symptoms persisted due to the depletion of odd-chain citric acid cycle intermediates, also called anaplerotic substrates. In other words, even-chain fatty acids could not provide all of the required citric acid cycle substrates for LC-FAOD patients.

DOJOLVI, an odd-chain MCT, solves that problem by replenishing citric acid cycle intermediates. Studies showed that, when comparing patients taking triheptanoin (C7) with trioctanoin (C8, traditional MCTs), those taking triheptanoin experienced less episodes and hospital stays related to hypoglycemia, cardiomyopathy, and rhabdomyolysis.

How it works

DOJOLVI is a medium-chain triglyceride (MCT) that consists of three odd-chain 7-carbon fatty acids. It can be used as a fuel source for patients with LC-FAOD, who cannot convert long-chain fatty acids into energy. DOJOLVI bypasses the LC-FAOD enzyme deficiencies.

Pancreatic enzymes in the intestine hydrolyze DOJOLVI into three 7-carbon fatty acids (heptanoate) and one glycerol molecule. Each 7-carbon fatty acid is further broken down into one 3-carbon (Propionyl CoA) and two 2-carbon (Acetyl CoA) molecules. These anaplerotic substrates allow the Krebs cycle, or citric acid cycle, to run without limitations.

In comparison, traditional MCT (odd-chain fatty acids), can supply only acetyl CoAs. Once the propionyl CoA is depleted, the citric acid cycle cannot run anymore and produce energy, or ATP.

Clinical trials with triheptanoin in LC-FAOD

  1. Double-blind, randomized controlled study

32 participants, Group 1 taking C7 and group 2 taking C8, for 4 months

Results: Patients in the C7 group had:

  • Increased left ventricular (LV) ejection fraction by 7.4% with a 20% decrease in LV wall mass
  • Lower heart rate for the same stress test
  • No difference in clinical outcomes (metabolic hospitalizations, cardiac function on resting ECG and treadmill ergometry, or metabolic biomarkers including glucose, insulin, lactate, total serum ketones, acylcarnitines, or serum free fatty-acid concentrations) due to the short duration of the study and the relative stability of the patients

2. Retrospective analysis of data of 20 patients treated with C7 in a compassionate use protocol for up to 13 years

Results after initiating C7:

  • Reduced mean hospitalization days (by 67%)
  • Close to no hypoglycaemic events with a significant reduction in events per year and hospital days per year

  1. Open-label, single-arm, phase 2 safety and efficacy study with C7:

End points were measured at 24 and 78 weeks.

Patients were their own control.

At 24 weeks, there was an increase in watts generated over baseline during the exercise tolerance test. The patients also reported an increased quality of life.

At 78 weeks, there was a reduction in the incidence of major clinical events (70 vs 39%) and hospital days due to rhabdomyolysis (55 vs 37%), hypoglycemia (12 vs 1%), and cardiomyopathy (3 vs 1%).

Why recently completed prospective studies demonstrate significant reduction on hypoglycemic events and improved cardiac function, but a less dramatic effect on muscle symptoms

With C7 (triheptanoin) and C8 (regular MCT), there is a possibility that the accumulation of abnormal long-chain fats (through elongation of medium-chain fatty acids) serve as a signal for inflammation and subsequent rhabdomyolysis.

ADDITIONAL INFORMATION ON THE USE OF DOJOLVI

For patients already taking another MCT product

Discontinue the other MCT product prior to the first dose of DOJOLVI.

Dosage and administration

The target dosage is up to 35% of the daily caloric intake (DCI). It is divided into a minimum of 4 daily doses.

Here is the formula to calculate the total daily dose (in ml):

= DCI (kcal) * Target __ % of DCI / 8.3kcal/ml

Initiate DOJOLVI at a total daily dosage of 10% DCI, and increase to up to 35% DCI over a period of 2-3 weeks.

DOJOLVI should be taken with food, during snacks, or meals to avoid side effects.

Pharmacokinetics

The time it takes DOJOLVI to reach the maximum concentration in the blood: 0.7-1.4 hours

Preparation

  1. To withdraw the prescribed volume, use an oral syringe or measuring cup made up of one of the following compatible materials: stainless steel, glass, high density polyethylene (HDPE), polypropylene, low density polyethylene, polyurethane or silicone.
  2. Mix DOJOLVI well with either semi-solid foods, liquids, or formula via a silicone or polyurethane feeding tube.
  3. Swallow the mixture.

Storage

Store DOJOLVI at room temperature, between 20-25 degrees Celsius (68°F – 77°F).

Use within 9 months of opening the bottle.

According to the monograph: The mixture can be stored for up to 24 hours in the refrigerator.

According to the study ‘Triheptanoin Stability in Foods, Formulas, and Emulsion’, ‘No appreciable differences in triheptanoin degradation were observed when mixed with beverages or foods and stored for up to 4 hours at 25 °C (77 °F) and 40 °C (104 °F), up to 48 hours at 2–8 °C (35.6–46.4 °F), or when baked in muffins at 200 °C (392 °F) and stored for up to 7 days’.

Missed dose

If a dose is missed, take the next dose as soon as possible with the following doses taken at 3-4 hour intervals. Skip the missed dose if it will not be possible to take all the prescribed doses in a day.

Common side effects

Abdominal pain (60%), diarrhea (44%), vomiting (44%), and nausea (14%)

Precautions

Avoid administering DOJOLVI in patients with pancreatic insufficiency. Low or absent pancreatic enzymes may reduce absorption.

Interactions

Pancreatic lipase inhibitors, such as orlistat, may reduce the absorption of DOJOLVI.

Special populations

Pregnant women: There is no available data.

However, studies were conducted with rats and rabbits during organogenesis (weeks 6-10, the period of time that the fetus’s important organs are developing). Lack of body weight gain with pregnant rats and rabbits was observed, however, it was associated with decreased food consumption due to food aversion.

Breastfeeding: There is no available data. MCTs are found in human breast milk.

References