Firdapse Active Ingredient 3,4‐DAP Targets Muscles in Rats, Has Long-Lasting Effect, Study Says

3,4‐diaminopyridine — the active ingredient of the only FDA-approved treatment for adults with Lambert-Eaton myasthenic syndrome (LEMS) — effectively targets muscles in rats and has a long-lasting effect in the body, a study says.

The findings of the study, “Pharmacokinetics and Tissue Distribution of 3,4‐Diaminopyridine in Rats,” were published in Biopharmaceuticals & Drug Disposition.

LEMS is an autoimmune disease that affects the neuromuscular junction — the region where motor neurons and muscle fibers communicate — and results in muscle weakness and reduced reflexes.

Treatment with 3,4‐diaminopyridine, known as 3,4‐DAP, helps restore communication between muscle cells. Since the 1980s, it has become the standard treatment for LEMS in the E.U. and the U.S.

A salt formulation of 3,4‐DAP called amifampridine phosphate — sold under the brand name Firdapse by Catalyst Pharmaceuticals — has been named an orphan drug for the treatment of LEMS. It was approved first by the European Medicines Agency (EMA) in 2010, and then by the U.S. Food and Drug Administration (FDA) in 2018.

However, little is known about its pharmacokinetics, or the way in which the medicine is absorbed, distributed, metabolized, and then eliminated from the body. To date, the pharmacokinetic properties of 3,4‐DAP have only been analyzed in animals receiving the compound orally and never through an intravenous route. In addition, very little is known about the way the compound is distributed in the body after being administered.

“Despite case-studies and randomized controlled studies that used 3,4-DAP for the treatment of LEMS, the pharmacokinetics of 3,4-DAP [in humans and animal models] have been rarely studied because it is an orphan drug for the treatment of a rare disease,” the investigators said.

To learn more, a team of researchers from the Kanazawa University in Japan set out to characterize the pharmacokinetic properties of 3,4‐DAP — especially its tissue distribution — when administered to rats. The 3,4-DAP was given by an intravenous, or into-the-vein injection in male rats at eight weeks of age.

On average, investigators found the compound had an half-life of 15.9 minutes after administration and a volume of distribution of 2.8 L/kg.

The half-life of a drug refers to the period of time it takes for the levels of the compound to drop to half; higher values indicate that a drug lasts longer in the body after being administered. The volume of distribution refers to the total “tissue volume” that would be needed in theory to contain the same amount of the drug found in the plasma; higher values indicate a drug has a wider tissue distribution.

“These results were similar to a previous report, and we considered that 3,4-DAP was distributed across tissues within several minutes after administration, achieved equilibrium, and was eliminated quickly,” the researchers said.

The team also found the tissue‐to‐plasma partition coefficient (Kp) — the ratio between the levels of a drug found in a tissue/organ and those found in the plasma — were higher in muscles, heart and kidneys. In pharmacokinetics, high Kp values indicate the levels of a drug found in a specific tissue/organ are higher than those found in the plasma; this is a strong indication this particular tissue/organ is the drug’s target.

Besides discovering the Kp value in muscles — a likely target tissue of 3,4‐DAP in LEMS patients — was high, they also found, based on calculations using the volumes of distribution, that more than 68% of the administered 3,4‐DAP had reached the muscles.

“These results support the concept that proteins in the muscle may bind 3,4-DAP. However, determination of the mechanism by which 3,4-DAP is distributed to muscle requires further study,” they said.