|Systematic (IUPAC) name|
|AHFS/Drugs.com||UK Drug Information|
|Metabolism||Acetylation to 3-N-acetylamifampridine|
|Biological half-life||2.5 hrs (amifampridine)
4 hrs (3-N-acetylamifampridine)
|Excretion||Renal (19% unmetabolized, 74–81% 3-N-acetylamifampridine|
|ATC code||N07XX05 (WHO)|
|Molar mass||109.13 g·mol−1|
|Melting point||218 to 220 °C (424 to 428 °F) decomposes|
|Solubility in water||24 mg/mL (20 °C)|
|(what is this?)|
The compound 3,4-diaminopyridine has the International Nonproprietary Name amifampridine and is used as a drug, predominantly in the treatment of a number of rare muscle diseases. The phosphate salt of amifampridine is a more stable formulation that does not require refrigeration; it is marketed in the EU by BioMarin Pharmaceutical under the trade name Firdapse and designated as an orphan drug in the EU. In the United States, amifampridine is under investigation for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) by Catalyst Pharmaceuticals, and was granted a breakthrough therapy designation by the FDA in 2013. In a Phase 3 clinical trial, it demonstrated superiority over placebo in both co-primary endpoints. LEMS patients can receive amifampridine at no cost under an ongoing expanded access program. A study to develop patient entry criteria for a clinical trial of the free base form of amifampridine has also been completed by Jacobus Pharmaceutical Company. This form remains available at no cost to patients with Lambert-Eaton myasthenic syndrome and congenital myasthenic syndromes under a long-standing compassionate use program, with FDA oversight, from Jacobus Pharmaceutical Company (see also Medical uses and Economics, below).
A 2011 systematic review from the Cochrane Collaboration found data favoring its use in LEMS. Although not approved for pharmaceutical use in the United States, amifampridine is available under compassionate use regulations for the treatment of LEMS.
Amifampridine is also used to treat many of the congenital myasthenic syndromes, particularly those with defects in choline acetyltransferase, downstream kinase 7, and those where any kind of defect causes "fast channel" behaviour of the acetylcholine receptor. In the US, amifampridine is under development as an orphan drug for congenital myasthenic syndrome and 3,4-diaminopyridine is available at no cost for patients with congenital myasthenic syndromes under a long-standing compassionate use program from Jacobus Pharmaceutical Co.
As amifampridine prolongs QT time, it is contraindicated in patients with congenital long QT syndrome and in patients that already take one or more QT prolonging drugs such as sultopride, disopyramide, cisapride, domperidone, rifampicin or ketoconazol. It is also contraindicated in patients with epilepsy or badly controlled asthma.
Little is known about side effects because the drug is only used for rare diseases. Reported side effects include paraesthesia (tingling or prickling sensations) and hypoaesthesia (numbness), especially periorally (around the mouth), as well as gastrointestinal side effects such as nausea and diarrhoea.
No systematic interaction studies have been conducted. Based on theoretic reasoning, other QT prolonging drugs may increase the risk of long QT syndrome and torsades de pointes (see contraindications above). Other drugs that lower the seizure threshold may increase the risk of seizures. Interactions via the liver's cytochrome P450 enzyme system are considered unlikely.
Mechanism of action
In Lambert-Eaton syndrome, acetylcholine release is inhibited as antibodies meant to target certain cancers target Ca2+ channels on the prejunctional membrane instead. Amifampridine works by blocking potassium channel efflux in nerve terminals so that action potential duration is increased. Ca2+ channels can then be open for a longer time and allow greater acetylcholine release to stimulate muscle at the end plate.
Amifampridine is quickly and almost completely (93–100%) absorbed from the gut. In a study with 91 healthy subjects, maximum amifampridine concentrations in blood plasma were reached after 0.6 (±0.25) hours when taken without food, or after 1.3 (±0.9) hours after a fatty meal, meaning that the speed of absorption varies widely. Biological half-life (2.5±0.7 hrs) and the area under the curve (AUC = 117±77 ng∙h/ml) also vary widely between subjects, but are nearly independent of food intake.
The substance is deactivated by acetylation via N-acetyltransferases to the single metabolite 3-N-acetylamifampridine. Activity of these enzymes (primarily N-acetyltransferase 2) in different individuals seems to be primarily responsible for the mentioned differences in half-life and AUC: the latter is increased up to 9-fold in slow metabolizers as compared to fast metabolizers.
Amifampridine is eliminated via the kidneys and urine to 74–81% as N-acetylamifampridine and to 19% in unchanged form.
Physical and chemical properties
3,4-Diaminopyridine is a pale yellow to pale brown crystalline powder that melts at about 218–220 °C (424–428 °F) under decomposition. It is readily soluble in methanol, ethanol and hot water, but only slightly in diethyl ether. Solubility in water at 20 °C (68 °F) is 25 g/L.
The drug formulation contains the phosphate salt, more specifically 4-aminopyridine-3-ylammonium dihydrogen phosphate. This salt forms prismatic, monoclinic crystals (space group C2/c) and is readily soluble in water.
Society and culture
The licensing of Firdapse in 2010 led to a sharp increase in price for the drug. In some cases, this has led to hospitals using an unlicensed form rather than the licensed agent, as the price difference proved prohibitive. BioMarin has been criticized for licensing the drug on the basis of previously conducted research, and yet charging exorbitantly for it. A group of UK neurologists and pediatricians have petitioned to prime minister David Cameron in an open letter to review the situation. The company responded that it submitted the licensing request at the suggestion of the French government, and points out that the increased cost of a licensed drug also means that it is monitored by regulatory authorities (e.g. for uncommon side effects), a process that was previously not present in Europe.
In the United States, both the phosphate and the free base have completed clinical trials to treat LEMS. Both formulations are available to LEMS patients in the U.S.: the free base is available to patients with LEMS and congenital myasthenic syndromes under a compassionate distribution program by Jacobus Pharmaceutical Company, and the phosphate salt is available to LEMS patients under an expanded access program by Catalyst Pharmaceuticals. Patients must be diagnosed with LEMS or congenital myasthenic syndrome and meet appropriate inclusion criteria.
Compounding pharmacies may also be a source of amifampridine in the U.S. In Europe, the phosphate is sold by BioMarin, and the free base is compounded, usually by hospital pharmacies.
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