Acetaminophen may compromise safety, efficacy of Firdapse: Study

Acetaminophen might lead to unwanted drug interactions with Firdapse

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People with Lambert-Eaton myasthenic syndrome (LEMS) should be cautious when taking Firdapse (amifampridine) together with acetaminophen, a common over-the-counter pain killer and fever reducer, to avoid unwanted interactions that could compromise how safe Firdapse is and how well it works, a study in rats suggests.

The study, “Investigation of N-Acetyltransferase 2-Mediated Drug Interactions of Amifampridine: In Vitro and In Vivo Evidence of Drug Interactions with Acetaminophen,” was published in the journal Pharmaceutics.

LEMS occurs when the immune system mistakenly attacks a protein on nerve cell endings, preventing the release of a signaling molecule called acetylcholine. Without acetylcholine, the signals nerve cells usually send to muscles to instruct them to contract are disrupted, leading to muscle weakness.

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Firdapse is the first and, so far, only oral medication approved in the U.S. to treat symptoms of LEMS in children and adults. It works by increasing the amount of acetylcholine that is released from nerve cell endings, thereby also enhancing muscle strength.

When people living with LEMS take Firdapse, their body processes its active ingredient, amifampridine, through a series of chemical reactions. This includes changing it to an inactive form, called 3-N-acetylamifampridine, that makes it easier to eliminate (excrete) when it is no longer needed. This is done by an enzyme called N-acetyltransferase 2 (NAT2).

Acetaminophen, also known as paracetamol, is used alone to relieve pain and fever or combined with other active ingredients in a long list of over-the-counter and prescription medications. While acetaminophen can block the activity of NAT2, it is unclear how this may affect how the enzyme processes amifampridine.

To know more, three researchers in Korea first set out some tests in test tubes containing a fraction of rat liver where enzymes like NAT2 are present. They found that the more amifampridine there was, the more 3-N-acetylamifampridine formed, until it reached a steady level or plateau.

The presence of acetaminophen, however, affected the amount of 3-N-acetylamifampridine that was formed. The more acetaminophen there was, the less 3-N-acetylamifampridine was formed. The researchers observed a similar, yet weaker effect, when they used a fraction of human or mouse liver.

Next, the researchers moved on to test the potential interactions in live rats. When they gave acetaminophen (100 mg/kg) to rats for about 10 minutes before giving them oral amifampridine (2 mg/kg), the amount of amifampridine in the bloodstream increased in the rats. Additionally, they observed that the ratio of 3-N-acetylamifampridine to amifampridine decreased.

Together, these findings indicated that amifampridine stayed in the body for a longer time and was not processed into 3-N-acetylamifampridine as quickly. When this happens, amifampridine can build up in the body to a level that can be toxic to the nervous system.

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Acetaminophen may affect how Firdapse is processed in the body

Additionally, the amount of amifampridine excreted in the urine and the amount distributed to different tissues — particularly to the liver, spleen, and muscles, but also to the kidneys, heart, lungs, and brain — was higher in rats given acetaminophen.

Overall, these findings indicate that when acetaminophen is taken together with Firdapse, it can lead to unwanted interactions that can affect how Firdapse is processed in the body.

“Acetaminophen co-administration may lead to relevant drug interactions with amifampridine; thus, care should be taken when co-administering amifampridine and acetaminophen,” the researchers wrote.