Amifampridine
Amifampridine Uses, Dosage, Side Effects, Food Interaction and all others data.
Amifampridine, or 3,4-diaminopyridine (3,4-DAP), is a quaternary ammonium compound that blocks presynaptic potassium channels, and subsequently prolongs the action potential and increases presynaptic calcium concentrations . It was first discovered in Scotland in the 1970s and its clinical effectiveness for neuromuscular disorders, including Lambert–Eaton myasthenic syndrome (LEMS), has been investigated in the 1980s . Amifampridine phosphate is a more stable salt that serves as an active ingredient of EMA-approved Firdapse, which was previously marketed as Zenas. It is currently used as the first-line symptomatic treatment for LEMS in adult patients and is ideally given as oral tablets in divided doses, three or four times a day. Firdapse (amifampridine) was formally approved by the US FDA for the treatment of adults with LEMS as recently as November of 2018 .
LEMS is a rare auto-immune disorder of the neuromuscular junction that is characterized by proximal muscle weakness, depressed tendon reflexes, and posttetanic potentiation in addition to autonomic dysfunction . About 50-60% of the patients develop more rapidly progressive LEMS and small cell lung cancer, which influences the prognosis . Patients with LEMS develop serum antibodies against presynaptic P/Q-type voltage-gated calcium channels, leading to decreased presynaptic calcium levels and reduced quantal release of acetylcholine, which is mainly responsible for causing symptoms of LEMS . Reduced acetylcholine release at the neuromuscular junction leads to decreased frequency of miniature endplate potentials of normal amplitude, and insufficient acetylcholine levels for the activation of postsynaptic muscle fibers following a single nerve impulse . This leads to the reduction of the compound muscle action potential (CMAP) . Treatment for LEMS include immunotherapy such as conventional immunosuppression or intravenous immunoglobulins, however such treatments are recommended in patients in whom symptomatic treatment would not suffice . Amifampridine is the nonimmune treatment options for LEMS.
In phase III clinical trials of adult patients with LEMS, treatment of amifampridine significantly improved symptoms of LEMS compared to placebo with good tolerance . It was demonstrated in clinical studies involving healthy volunteers that the pharmacokinetics and systemic exposure to amifampridine is affected by the genetic differences in N-acetyl-transferase (NAT) enzymes (acetylator phenotype) and NAT2 genotype, which is subject to genetic variation . Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache .
| Trade Name | Amifampridine |
| Availability | Prescription only |
| Generic | Amifampridine |
| Amifampridine Other Names | 3,4-DAP, 3,4-Diaminopyridine, 3,4-Pyridinediamine, 4,5-Diaminopyridine, Amifampridine |
| Related Drugs | Firdapse, Ruzurgi |
| Weight | 10mg |
| Type | Oral tablet |
| Formula | C5H7N3 |
| Weight | Average: 109.132 Monoisotopic: 109.063997237 |
| Protein binding | There is no human data on serum protein binding of amifampridine . |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Amifampridine is a voltage gated potassium channel blocker used to treat Lambert-Eaton myasthenic syndrome.
Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and in patients aged 6 to less than 17 years of age. Nevertheless, it is important to note that at the current time only the Firdapse brand of amifampridine is indicated for the treatment of LEMS in adults and the Ruzurgi brand of amifampridine is indicated for the treatment of LEMS in patients aged 6 to less than 17 years.
Amifampridine is also used to associated treatment for these conditions: Lambert-Eaton Myasthenic Syndrome (LEMS)
How Amifampridine works
Amifampridine is a symptomatic treatment that increases acetylcholine concentrations at the neuromuscular junction. It selectively blocks presynaptic fast voltage-gated potassium channels, thereby prolonging cell membrane depolarization and action potential, and augmenting calcium transport into the nerve endings. Increased intracellular calcium enhances the exocytosis of acetylcholine-containing vesicles and enhances impulse transmission at central, autonomic, and neuromuscular synapses . Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV .
Toxicity
The approximate oral LD50 was >25mg/kg in rats and 100 mg/kg in mice. The approximate intravenous LD50 was 25 mg/kg in both rats and mice . Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively . There is limited clinical experienced with amifampridine overdose. The manifestations of acute drug overdose may include abdominal pain, and should be responded with discontinuation of treatment and initiation of supportive care with close monitoring of viral signs. There is no specific antidote known for amifampridine .
In vitro, amifampridine showed no clinically relevant carcinogenic or genotoxic potential. However, in a 2-year rat study, amifampridine caused small but statistically significant dose-related increases in the incidence of Schwannomas in both genders and of endometrial carcinomas in females . At doses higher than the recommended daily dose for humans, amifampridine caused a dose-related increase in the percentage of pregnant rats with stillborn offspring . Effects on the central and autonomic nervous system, increased liver and kidney weights and cardiac effects (second degree atrioventricular block) were seen in a repeat-dose toxicity studies in rats and dogs .
Food Interaction
- Take with or without food.
Amifampridine Drug Interaction
Moderate: lithiumUnknown: lactobacillus acidophilus, charcoal, sulfamethoxazole / trimethoprim, ubiquinone, copper gluconate, glucose, diltiazem, alendronate, glycerin, heparin, sodium iodide, arginine, levocarnitine, cysteine, metoprolol, metoprolol, acetaminophen, bioflavonoids, cholecalciferol
Amifampridine Disease Interaction
Volume of Distribution
In rats, orally-administered amifampridine was extensively absorbed in the gastrointestinal tract and widely distributed. Drug concentrations were highest in organs of excretion, including liver, kidney and the gastrointestinal tract, and some tissues of glandular function, such as lacrimal, salivary, mucous, pituitary and thyroid glands . Concentrations in tissues are generally similar to or greater than concentrations in plasma .
Elimination Route
Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours . A single oral dose of 20 mg amifampridine in fasted individuals resulted in mean peak plasma concentrations (Cmax) ranging from 16 to 137 ng/mL . Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine . Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax) . It is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios .
Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype . The NAT enzymes are highly polymorphic that results in variable slow acetylator (SA) and rapid acetylator (RA) phenotypes. Slow acetylators are more prone to increased systemic exposure to amifampridine, and may require higher doses for therapeutic efficacy .
Half Life
The plasma elimination half-life is approximately 2.5 hours for amifampridine and 4 hours for 3-N-acetylamifampridine .
Clearance
Overall clearance of amifampridine is both metabolic and renal; it is mostly cleared from the plasma via metabolism by N-acetylation .
Elimination Route
Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours . About 19% of the total renally-excreted dose is in the parent drug form, and about 74-81.7% of the dose is in its metabolite form .
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