Amifampridine

我dentification

Summary

Amifampridineis 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 concentrations¹．我t 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 1980s⁶．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 2018⁷．

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 dysfunction¹．About 50-60% of the patients develop more rapidly progressive LEMS and small cell lung cancer, which influences the prognosis¹．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 LEMS¹．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 impulse¹．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 suffice¹．Amifampridine is the nonimmune treatment options for LEMS.

我n phase III clinical trials of adult patients with LEMS, treatment of amifampridine significantly improved symptoms of LEMS compared to placebo with good tolerance²．我t 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 variation¹²．Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache¹²．

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOL SDF 3D-SDF PDB SMILES 我nChI

Similar Structures

Structure for Amifampridine (DB11640)

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Weight

Average: 109.132
Monoisotopic: 109.063997237

Chemical Formula

C₅H₇N₃

Synonyms

• 3,4-DAP
• 3,4-Diaminopyridine
• 3,4-Pyridinediamine
• 4,5-Diaminopyridine
• Amifampridine
• DAP

External IDs

• NSC-521760

Pharmacology

我ndication

Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and pediatric patients.¹¹Nevertheless, 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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Associated Conditions

• Lambert Eaton Myasthenic Syndrome (LEMS)

Contraindications & Blackbox Warnings

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Pharmacodynamics

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) score¹．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 reported¹．我n vitro, amifampridine was shown to modulate cardiac conduction and induce phasic contractions in different arteries from several species¹．我n addition, it stimulated potassium-evoked dopamine and noradrenaline release in rat hippocampal slices and upregulate acetylcholine release in the brain¹．我t may also potentiate adrenergic and cholinergic neuromuscular transmission in the gatrointestinal tract¹．我n a single pharmacokinetic study, no effect was observed of amifampridine phosphate on cardiac repolarization as assessed using the QTc interval¹²．There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations¹²．

的作用机制

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^1,12．Amifampridine提高肌肉力量和resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV¹²．

Target	Actions	Organism
APotassium voltage-gated channel subfamily A member 1	blocker	Humans

Absorption

Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours¹²．A single oral dose of 20 mg amifampridine in fasted individuals resulted in mean peak plasma concentrations (Cmax) ranging from 16 to 137 ng/mL¹²．Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine¹²．Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax)³．我t is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios¹²．

Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype⁴．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^4,12．

Volume of distribution

我n healthy volunteers, the volume of distribution for plasma amifampridine indicated that RUZURGI is a drug with a moderate to a high volume of distribution.⁹After a 2 mg/kg infusion in rats, the volume of distribution at steady-state was 2.8 ± 0.7 L/kg.⁵Drug 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 glands¹²．Concentrations in tissues are generally similar to or greater than concentrations in plasma¹²．

Protein binding

我n 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

Hover over products below to view reaction partners

• Amifampridine
  • 3-N-acetylamifampridine

Route of elimination

Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours³．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 form¹²．

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-acetylation¹²．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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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 mice¹³．Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively¹．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 amifampridine¹²．

我n 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 females¹²．At doses higher than the recommended daily dose for humans, amifampridine caused a dose-related increase in the percentage of pregnant rats with stillborn offspring¹²．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 dogs¹²．

Pathways

Not Available

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我nteractions

Drug InteractionsLearn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• 我llicit
• Withdrawn
• 我nvestigational
• Experimental
• All Drugs

Drug	我nteraction
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Acrivastine	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.
Alfuzosin	The risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Amifampridine.
Alimemazine	The risk or severity of QTc prolongation can be increased when Alimemazine is combined with Amifampridine.
Amantadine	The risk or severity of QTc prolongation can be increased when Amantadine is combined with Amifampridine.
Ambenonium	The risk or severity of adverse effects can be increased when Ambenonium is combined with Amifampridine.
Aminophylline	The risk or severity of seizure can be increased when Aminophylline is combined with Amifampridine.
Amiodarone	The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Amiodarone.
Amisulpride	The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Amisulpride.

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Food Interactions

• Take with or without food.

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Product Ingredients

我ngredient	UNII	CAS	我nChI Key
Amifampridine phosphate	8HF8FIN815	446254-47-3	KAICRBBQCRKMPO-UHFFFAOYSA-N

我nternational/Other Brands

Firdapse/Zenas

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	我mage
Amifampridine Serb	Tablet	10 mg	Oral	Serb Sa	2022-06-01	Not applicable
Amifampridine Serb	Tablet	10 mg	Oral	Serb Sa	2022-06-01	Not applicable
Amifampridine Serb	Tablet	10 mg	Oral	Serb Sa	2022-06-01	Not applicable
Firdapse	Tablet	10 mg	Oral	Serb Sa	2020-12-20	Not applicable
Firdapse	Tablet	10 mg	Oral	Kye Pharmaceuticals Inc.	2020-10-23	Not applicable
Firdapse	Tablet	10 mg/1	Oral	Catalyst Pharmaceuticals, Inc.	2019-01-07	Not applicable
Ruzurgi	Tablet	10 mg/1	Oral	Jacobus Pharmaceutical Company,Inc	2019-07-02	2023-11-30
Ruzurgi	Tablet	10 mg	Oral	Medunik Canada	2020-09-24	Not applicable

Categories

ATC Codes

N07XX05 — Amifampridine

• N07XX — Other nervous system drugs
• N07X — OTHER NERVOUS SYSTEM DRUGS
• N07 — OTHER NERVOUS SYSTEM DRUGS
• N — NERVOUS SYSTEM

Drug Categories

• Amines
• Aminopyridines
• Membrane Transport Modulators
• Miscellaneous Central Nervous System Agents
• Moderate Risk QTc-Prolonging Agents
• OCT2 Inhibitors
• Peripheral Nervous System Agents
• Potassium Channel Blockers
• Pyridines
• QTc Prolonging Agents

Chemical TaxonomyProvided byClassyfire

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

我nChI Key

OYTKINVCDFNREN-UHFFFAOYSA-N

我nChI

我nChI=1S/C5H7N3/c6-4-1-2-8-3-5(4)7/h1-3H,7H2,(H2,6,8)

我UPAC Name

pyridine-3,4-diamine

SMILES

NC1=CC=NC=C1N

References

General References

1. 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]
2. 哦,SJ, Shcherbakova N, Kostera-Pruszczyk 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]
3. 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]
4. 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]
5. 我shida 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]
6. Harvard Law Blog: Jacobus and Catalyst Continue to Race for Approval of LEMS Drug [Link]
7. US FDA [Link]
8. FDA NEWS RELEASE: FDA approves first treatment for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder [Link]
9. FDA Approved Drug Products: RUZURGI (amifampridine) tablets [Link]
10. FDA Approved Drug Products: FIRDAPSE (amifampridine) tablets [Link]
11. FDA Approved Drug Products: FIRDAPSE (amifampridine) tablets 2022 [Link]
12. FIRDAPSE (amifampridine) SUMMARY OF PRODUCT CHARACTERISTICS (EMA Label) [File]
13. European Medicines Agency (EMA) Assessment Report for Zenas (INN-amifampridine) [File]
14. RUZURGI (amifampridine) 2019 US FDA Label [File]

External Links

Human Metabolome Database

HMDB0246022

ChemSpider

5705

BindingDB

50416493

RxNav

2106338

ChEBI

135948

ChEMBL

CHEMBL354077

ZINC

ZINC000000164000

PDBe Ligand

L89

Wikipedia

Amifampridine

PDB Entries

5now

FDA label

Download (574 KB)

Clinical Trials

Clinical TrialsLearn More" title="" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Myasthenia Gravis, MuSK	1
3	Completed	Treatment	Generalized Myasthenia Gravis	1
3	Completed	Treatment	Lambert Eaton Myasthenic Syndrome (LEMS)	2
3	Completed	Treatment	Multiple Sclerosis	1
3	Completed	Treatment	Myasthenic Syndromes, Congenital	1
2	Completed	Treatment	Fatigue/Multiple Sclerosis	1
2	Completed	Treatment	Lambert Eaton Myasthenic Syndrome (LEMS)	1
2	Completed	Treatment	Spinal Muscular Atrophy (SMA)	1
2	Recruiting	Treatment	Post-BOTOX Vocal Weakness	1
2	Terminated	Treatment	Muscle Weakness	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
US11060128	No	2021-07-13	2032-06-29
US11274332	No	2012-06-29	2032-06-29
US11274331	No	2012-06-29	2032-06-29
US11268128	No	2012-06-29	2032-06-29
US10626088	No	2020-04-21	2037-02-25

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	是的	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

Spectrum	Spectrum Type	Splash Key
GC-MS Spectrum - EI-B	GC-MS	splash10-0a4i-9500000000-a63c0bd9a1bb53b616fd
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details 1.Potassium voltage-gated channel subfamily A member 1

Kind

Protein

Organism

Humans

Pharmacological action

是的

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

分子Weight

56465.01 Da

References

1. Kleopa KA: Autoimmune channelopathies of the nervous system. Curr Neuropharmacol. 2011 Sep;9(3):458-67. doi: 10.2174/157015911796557966. [Article]
2. 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]

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Drug created at October 17, 2016 21:29 / Updated at April 30, 2023 03:04