Identification

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Name
Amifampridine
Accession Number
DB11640
Type
Small Molecule
Groups
Approved, Investigational
Description

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 5. 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 6.

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 8. Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache 8.

Structure
Thumb
Synonyms
  • 3,4-DAP
  • 3,4-Diaminopyridine
  • 3,4-Pyridinediamine
  • 4,5-Diaminopyridine
  • DAP
External IDs
NSC-521760
Product Ingredients
IngredientUNIICASInChI Key
Amifampridine phosphate8HF8FIN815446254-47-3KAICRBBQCRKMPO-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FirdapseTablet10 mg/1OralCatalyst Pharmaceuticals, Inc.2019-01-07Not applicableUs
RuzurgiTablet10 mg/1OralJacobus Pharmaceutical Company, Inc.2019-06-27Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
RU4S6E2G0J
CAS number
54-96-6
Weight
Average: 109.132
Monoisotopic: 109.063997237
Chemical Formula
C5H7N3
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
4-imino-1,4-dihydropyridin-3-amine
SMILES
NC1=CNC=CC1=N

Pharmacology

Indication

Amifampridine is indicated for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults8 and in patients aged 6 to less than 17 years of age.10,7 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 adults8 and the Ruzurgi brand of amifampridine is indicated for the treatment of LEMS in patients aged 6 to less than 17 years.10,7

Associated Conditions
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) 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 8. There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations 8.

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 1,8. Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV 8.

TargetActionsOrganism
APotassium voltage-gated channel subfamily A member 1
blocker
Humans
Additional Data Available
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Absorption

Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours 8. 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 8. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine 8. 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 8.

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 4,8.

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 8. Concentrations in tissues are generally similar to or greater than concentrations in plasma 8.

Protein binding

There is no human data on serum protein binding of amifampridine 1.

Metabolism

3-N-acetylated amifampridine is the major metabolite based on in vivo and in vitro human studies 8.

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 8.

Half life

The plasma elimination half-life is approximately 2.5 hours for amifampridine and 4 hours for 3-N-acetylamifampridine 8.

Clearance

Overall clearance of amifampridine is both metabolic and renal; it is mostly cleared from the plasma via metabolism by N-acetylation 8.

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 9. 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 8.

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 8. 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 8. 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 8.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1,10-PhenanthrolineThe risk or severity of adverse effects can be increased when 1,10-Phenanthroline is combined with Amifampridine.
AbexinostatThe risk or severity of QTc prolongation can be increased when Amifampridine is combined with Abexinostat.
AcebutololThe risk or severity of QTc prolongation can be increased when Acebutolol is combined with Amifampridine.
AceprometazineThe risk or severity of QTc prolongation can be increased when Aceprometazine is combined with Amifampridine.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Acetyldigoxin is combined with Amifampridine.
AcotiamideThe risk or severity of adverse effects can be increased when Acotiamide is combined with Amifampridine.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Amifampridine.
AdenosineThe risk or severity of QTc prolongation can be increased when Adenosine is combined with Amifampridine.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Amifampridine.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Amifampridine.
Additional Data Available
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Food Interactions
Not Available

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. [PubMed:21822385]
  2. 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. [PubMed:26852139]
  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. [PubMed:26101174]
  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. [PubMed:28641995]
  5. Harvard Law Blog: Jacobus and Catalyst Continue to Race for Approval of LEMS Drug [Link]
  6. US FDA [Link]
  7. FDA NEWS RELEASE: FDA approves first treatment for children with Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder [Link]
  8. FIRDAPSE (amifampridine) SUMMARY OF PRODUCT CHARACTERISTICS (EMA Label) [File]
  9. European Medicines Agency (EMA) Assessment Report for Zenas (INN-amifampridine) [File]
  10. RUZURGI (amifampridine) 2019 US FDA Label [File]
External Links
ChemSpider
5705
BindingDB
50416493
ChEBI
135948
ChEMBL
CHEMBL354077
HET
L89
Wikipedia
Amifampridine
ATC Codes
N07XX05 — Amifampridine
PDB Entries
5now
FDA label
Download (574 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentDisseminated Sclerosis / Tiredness1
2Enrolling by InvitationTreatmentMuscle Wasting1
2RecruitingTreatmentMuscular Atrophy, Spinal1
2TerminatedTreatmentMuscle Weakness1
2Unknown StatusTreatmentEaton-Lambert Myasthenic Syndrome / Lambert-Eaton Myasthenic Syndrome (LEMS)1
2, 3CompletedNot AvailableBotulism1
3CompletedTreatmentDisseminated Sclerosis1
3CompletedTreatmentLambert Eaton Myasthenic Syndrome (LEMS)1
3CompletedTreatmentLambert-Eaton Myasthenic Syndrome (LEMS)1
3RecruitingTreatmentMyasthenia Gravis, Generalized1
3RecruitingTreatmentMyasthenia Gravis, MuSK1
3RecruitingTreatmentMyasthenic Syndromes, Congenital1
Not AvailableAvailableNot AvailableCongenital Myasthenia (CM) / Lambert-Eaton Myasthenic Syndrome (LEMS)1
Not AvailableAvailableNot AvailableCongenital Myasthenic Syndrome / Downbeat Nystagmus / Lambert-Eaton Myasthenic Syndrome (LEMS)1
Not AvailableAvailableNot AvailableCongenital Myasthenic Syndrome / Lambert-Eaton Myasthenic Syndrome (LEMS)1
Not AvailableCompletedNot AvailableInfection Related to Vascular Prothesis / Infection Related to Ventricular Assist Device / Infective Endocarditis / Mediastinitis / Surgical Site Infections1
Not AvailableCompletedTreatmentLambert-Eaton Myasthenic Syndrome (LEMS)1
Not AvailableNo Longer AvailableNot AvailableLambert Eaton Myasthenic Syndrome (LEMS)1
Not AvailableNo Longer AvailableNot AvailableLambert Eaton Myasthenic Syndrome (LEMS) / Myasthenic Syndromes, Congenital1
Not AvailableRecruitingTreatmentCongenital Myasthenic Syndrome / Lambert-Eaton Myasthenic Syndrome (LEMS)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
TabletOral10 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)229 ± 2EMA Assessment Report
water solubilitySolubleEMA Assessment Report
Predicted Properties
PropertyValueSource
Water Solubility5.8 mg/mLALOGPS
logP-1.5ALOGPS
logP-0.6ChemAxon
logS-1.3ALOGPS
pKa (Strongest Acidic)15.5ChemAxon
pKa (Strongest Basic)11.81ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area61.9 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity43.71 m3·mol-1ChemAxon
Polarizability11.03 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - EI-BGC-MSsplash10-0a4i-9500000000-a63c0bd9a1bb53b616fd
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Aminopyridine / Heteroaromatic compound / Azacycle / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative / Primary amine / Organonitrogen compound / Amine / Aromatic heteromonocyclic compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

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
  1. Kleopa KA: Autoimmune channelopathies of the nervous system. Curr Neuropharmacol. 2011 Sep;9(3):458-67. doi: 10.2174/157015911796557966. [PubMed:22379460]
  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. [PubMed:21822385]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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
  1. 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. [PubMed:28641995]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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
  1. 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. [PubMed:28641995]

Drug created on October 17, 2016 15:29 / Updated on July 13, 2019 00:57