Identification
- Summary
Amifampridine is a voltage gated potassium channel blocker used to treat Lambert-Eaton myasthenic syndrome.
- Brand Names
- Firdapse, Ruzurgi
- Generic Name
- Amifampridine
- DrugBank Accession Number
- DB11640
- Background
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 1. 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 6. 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 7.
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 1. About 50-60% of the patients develop more rapidly progressive LEMS and small cell lung cancer, which influences the prognosis 1. 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 1. 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 1. This leads to the reduction of the compound muscle action potential (CMAP) 1. 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 1. 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 2. 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 13. Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache 13.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Amifampridine (DB11640)
- Weight
- Average: 109.132
Monoisotopic: 109.063997237 - Chemical Formula
- C5H7N3
- Synonyms
- 3,4 diaminopyridine
- 3,4-DAP
- 3,4-Diaminopyridine
- 3,4-Pyridinediamine
- 4,5-Diaminopyridine
- Amifampridine
- DAP
- External IDs
- NSC-521760
Pharmacology
- Indication
Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients.11 Nevertheless, at the current time only the Firdapse brand of amifampridine is indicated for the treatment of LEMS in both adult and pediatric patients, while the Ruzurgi brand of amifampridine is indicated for the treatment of LEMS only in patients aged 6 to less than 17 years.11,9
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Lambert-eaton myasthenic syndrome •••••••••••• •••• •••• •• ••••• •• ••• ••••••• ••••••• ••• •••••••••• Treatment of Lambert-eaton myasthenic syndrome (lems) •••••••••••• •••••• ••••••••• ••••••• ••••••• ••• •••••••••• - Contraindications & Blackbox Warnings
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Administration of amifampridine to patients with LES in clinical trials resulted in improvement of the compound muscle action potential (CMAP), muscle function, and quantitative myasthenia gravis (QMG) score 1. One case of a slight prolongation of the QTc interval in male patient with LEMS and euthyroid Hashimoto’s disease treated with 90 mg of amifampridine in combination with 100 mg azathioprine was reported 1. In vitro, amifampridine was shown to modulate cardiac conduction and induce phasic contractions in different arteries from several species 1. In addition, it stimulated potassium-evoked dopamine and noradrenaline release in rat hippocampal slices and upregulate acetylcholine release in the brain 1. It may also potentiate adrenergic and cholinergic neuromuscular transmission in the gatrointestinal tract 1. In a single pharmacokinetic study, no effect was observed of amifampridine phosphate on cardiac repolarization as assessed using the QTc interval 13. There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations 13.
- Mechanism of action
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 1,13. Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV 13.
Target Actions Organism APotassium voltage-gated channel subfamily A member 1 blockerHumans - Absorption
Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours 13. 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 13. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine 13. Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax) 3. It is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios 13.
Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype 4. 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 4,13.
- Volume of distribution
In healthy volunteers, the volume of distribution for plasma amifampridine indicated that RUZURGI is a drug with a moderate to a high volume of distribution.9 After a 2 mg/kg infusion in rats, the volume of distribution at steady-state was 2.8 ± 0.7 L/kg.5 Drug concentrations were highest in organs of excretion, including the liver, kidney, and the gastrointestinal tract, and some tissues of glandular function, such as lacrimal, salivary, mucous, pituitary, and thyroid glands 13. Concentrations in tissues are generally similar to or greater than concentrations in plasma 13.
- Protein binding
In vitro human plasma protein binding of amifampridine and 3-N-acetyl amifampridine was 25.3% and 43.3%, respectively.9
- Metabolism
Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite.11
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- Route of elimination
Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours 3. 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 13.
- Half-life
The average elimination half-life of amifampridine was 3.6 to 4.2 hours and 4.1 to 4.8 hours for the 3-N-acetyl amifampridine metabolite.9
- Clearance
Overall clearance of amifampridine is both metabolic and renal; it is primarily cleared from the plasma via metabolism by N-acetylation 13. Following oral administration of a single 20 or 30 mg dose of RUZURGI to healthy volunteers, amifampridine apparent oral clearance (CL/F) was 149 to 214 L/h.9
- Adverse Effects
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The approximate oral LD50 was >25mg/kg in rats and 100 mg/kg in mice.12 The approximate intravenous LD50 was 25 mg/kg in both rats and mice.12 Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively.1 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 13.
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 13. 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 13. 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 13.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAcrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Amifampridine. Adenosine The risk or severity of QTc prolongation can be increased when Adenosine is combined with Amifampridine. Ajmaline The risk or severity of QTc prolongation can be increased when Ajmaline is combined with Amifampridine. Albuterol The risk or severity of QTc prolongation can be increased when Salbutamol is combined with Amifampridine. Alfuzosin The risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Amifampridine. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Amifampridine phosphate 8HF8FIN815 446254-47-3 KAICRBBQCRKMPO-UHFFFAOYSA-N - International/Other Brands
- Firdapse / Zenas
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Amifampridine Serb Tablet 10 mg Oral Serb Sa 2022-06-01 Not applicable EU 
Amifampridine Serb Tablet 10 mg Oral Serb Sa 2022-06-01 Not applicable EU Amifampridine Serb Tablet 10 mg Oral Serb Sa 2022-06-01 Not applicable EU Firdapse Tablet 10 mg Oral Serb Sa 2020-12-20 Not applicable EU Firdapse Tablet 10 mg/1 Oral Catalyst Pharmaceuticals, Inc. 2019-01-07 Not applicable US 
Categories
- ATC Codes
- N07XX05 — Amifampridine
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as aminopyridines and derivatives. These are organic heterocyclic compounds containing an amino group attached to a pyridine ring.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Pyridines and derivatives
- Sub Class
- Aminopyridines and derivatives
- Direct Parent
- Aminopyridines and derivatives
- Alternative Parents
- Heteroaromatic compounds / Azacyclic compounds / Primary amines / Organopnictogen compounds / Hydrocarbon derivatives
- Substituents
- Amine / Aminopyridine / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound / Primary amine
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- RU4S6E2G0J
- CAS number
- 54-96-6
- InChI Key
- OYTKINVCDFNREN-UHFFFAOYSA-N
- InChI
- InChI=1S/C5H7N3/c6-4-1-2-8-3-5(4)7/h1-3H,7H2,(H2,6,8)
- IUPAC Name
- pyridine-3,4-diamine
- SMILES
- NC1=CC=NC=C1N
References
- General References
- Lindquist S, Stangel M: Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine. Neuropsychiatr Dis Treat. 2011;7:341-9. doi: 10.2147/NDT.S10464. Epub 2011 May 30. [Article]
- Oh SJ, Shcherbakova N, Kostera-Pruszczyk A, Alsharabati M, Dimachkie M, Blanco JM, Brannagan T, Lavrnic D, Shieh PB, Vial C, Meisel A, Komoly S, Schoser B, Sivakumar K, So Y: Amifampridine phosphate (Firdapse((R))) is effective and safe in a phase 3 clinical trial in LEMS. Muscle Nerve. 2016 May;53(5):717-25. doi: 10.1002/mus.25070. Epub 2016 Mar 3. [Article]
- Haroldsen PE, Musson DG, Hanson B, Quartel A, O'Neill CA: Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults. Clin Ther. 2015 Jul 1;37(7):1555-63. doi: 10.1016/j.clinthera.2015.05.498. Epub 2015 Jun 20. [Article]
- Haroldsen PE, Sisic Z, Datt J, Musson DG, Ingenito G: Acetylator Status Impacts Amifampridine Phosphate (Firdapse) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function. Clin Ther. 2017 Jul;39(7):1360-1370. doi: 10.1016/j.clinthera.2017.05.353. Epub 2017 Jun 19. [Article]
- Ishida N, Kondo Y, Chikano Y, Kobayashi-Nakade E, Suga Y, Ishizaki J, Komai K, Matsushita R: Pharmacokinetics and tissue distribution of 3,4-diaminopyridine in rats. Biopharm Drug Dispos. 2019 Sep;40(8):294-301. doi: 10.1002/bdd.2203. [Article]
- Harvard Law Blog: Jacobus and Catalyst Continue to Race for Approval of LEMS Drug [Link]
- US FDA [Link]
- FDA NEWS RELEASE: FDA approves first treatment for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder [Link]
- FDA Approved Drug Products: RUZURGI (amifampridine) tablets [Link]
- FDA Approved Drug Products: FIRDAPSE (amifampridine) tablets [Link]
- FDA Approved Drug Products: FIRDAPSE (amifampridine) tablets 2022 [Link]
- EMA Public Assessment Report: Zenas (INN-amifampridine) [Link]
- FIRDAPSE (amifampridine) SUMMARY OF PRODUCT CHARACTERISTICS (EMA Label) [File]
- European Medicines Agency (EMA) Assessment Report for Zenas (INN-amifampridine) [File]
- RUZURGI (amifampridine) 2019 US FDA Label [File]
- External Links
- Human Metabolome Database
- HMDB0246022
- ChemSpider
- 5705
- BindingDB
- 50416493
- 2106338
- ChEBI
- 135948
- ChEMBL
- CHEMBL354077
- ZINC
- ZINC000000164000
- PDBe Ligand
- L89
- Wikipedia
- Amifampridine
- PDB Entries
- 5now
- FDA label
- Download (574 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Muscle-specific tyrosine kinase (MuSK) myasthenia gravis 1 3 Completed Treatment Congenital Myasthenia (CM) 1 3 Completed Treatment Generalized Myasthenia Gravis 1 3 Completed Treatment Lambert Eaton Myasthenic Syndrome (LEMS) 2 3 Completed Treatment Multiple Sclerosis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet Oral 10 mg Tablet Oral 10 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10793893 No 2020-10-06 2034-04-07 US US11060128 No 2021-07-13 2032-06-29 US US11274332 No 2012-06-29 2032-06-29 US US11274331 No 2012-06-29 2032-06-29 US US11268128 No 2012-06-29 2032-06-29 US US10626088 No 2020-04-21 2037-02-25 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 229 ± 2 EMA Assessment Report water solubility freely soluble in water, and slightly soluble in solvents ethanol, methanol and acetic acid L43312 - Predicted Properties
Property Value Source Water Solubility 159.0 mg/mL ALOGPS logP -0.48 ALOGPS logP -0.9 Chemaxon logS 0.16 ALOGPS pKa (Strongest Basic) 9.25 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 64.93 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 33.3 m3·mol-1 Chemaxon Polarizability 10.94 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 115.4248579 predictedDarkChem Lite v0.1.0 [M-H]- 124.40396 predictedDeepCCS 1.0 (2019) [M+H]+ 115.1814579 predictedDarkChem Lite v0.1.0 [M+H]+ 126.412796 predictedDeepCCS 1.0 (2019) [M+Na]+ 115.6991579 predictedDarkChem Lite v0.1.0 [M+Na]+ 134.7598 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Blocker
- General Function
- Voltage-gated potassium channel activity
- Specific Function
- Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney (PubMed:1990381...
- Gene Name
- KCNA1
- Uniprot ID
- Q09470
- Uniprot Name
- Potassium voltage-gated channel subfamily A member 1
- Molecular Weight
- 56465.01 Da
References
- Kleopa KA: Autoimmune channelopathies of the nervous system. Curr Neuropharmacol. 2011 Sep;9(3):458-67. doi: 10.2174/157015911796557966. [Article]
- Lindquist S, Stangel M: Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine. Neuropsychiatr Dis Treat. 2011;7:341-9. doi: 10.2147/NDT.S10464. Epub 2011 May 30. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Arylamine n-acetyltransferase activity
- Specific Function
- Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivat...
- Gene Name
- NAT1
- Uniprot ID
- P18440
- Uniprot Name
- Arylamine N-acetyltransferase 1
- Molecular Weight
- 33898.445 Da
References
- Haroldsen PE, Sisic Z, Datt J, Musson DG, Ingenito G: Acetylator Status Impacts Amifampridine Phosphate (Firdapse) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function. Clin Ther. 2017 Jul;39(7):1360-1370. doi: 10.1016/j.clinthera.2017.05.353. Epub 2017 Jun 19. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Arylamine n-acetyltransferase activity
- Specific Function
- Participates in the detoxification of a plethora of hydrazine and arylamine drugs. Catalyzes the N- or O-acetylation of various arylamine and heterocyclic amine substrates and is able to bioactivat...
- Gene Name
- NAT2
- Uniprot ID
- P11245
- Uniprot Name
- Arylamine N-acetyltransferase 2
- Molecular Weight
- 33542.235 Da
References
- Haroldsen PE, Sisic Z, Datt J, Musson DG, Ingenito G: Acetylator Status Impacts Amifampridine Phosphate (Firdapse) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function. Clin Ther. 2017 Jul;39(7):1360-1370. doi: 10.1016/j.clinthera.2017.05.353. Epub 2017 Jun 19. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Quaternary ammonium group transmembrane transporter activity
- Specific Function
- Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creat...
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- FDA Approved Drug Products: RUZURGI (amifampridine) tablets [Link]
Drug created at October 17, 2016 21:29 / Updated at April 23, 2024 11:38