NAV

Amifampridine

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 12. Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache 12.

Type
Small Molecule
Groups
Approved, Investigational
Structure
3D
Similar Structures
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
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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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofLambert-eaton myasthenic syndrome•••••••••••••••• •••• •• ••••• •• •••••••••• ••••••• ••• ••••••••••
Treatment ofLambert-eaton myasthenic syndrome (lems)•••••••••••••••••• •••••••••••••••• ••••••• ••• ••••••••••
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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) 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 12. There were no changes in heart rate, atrioventricular conduction or cardiac depolarization as measured by the heart rate, PR and QRS interval durations 12.

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 1,12. Amifampridine improves muscle strength and resting compound muscle action potential (CMAP) amplitudes with an overall weighted mean difference of 1.69 mV 12.

TargetActionsOrganism
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 hours 12. 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 12. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine 12. 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 12.

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 4,12.

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 12. Concentrations in tissues are generally similar to or greater than concentrations in plasma 12.

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 12.

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 12. 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 mice 13. 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 12.

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 12. 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 12. 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 12.

Pathways
Not Available
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Not Available

Interactions

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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.
DrugInteraction
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interactions in your software
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.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Amifampridine.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Amifampridine phosphate8HF8FIN815446254-47-3KAICRBBQCRKMPO-UHFFFAOYSA-N
International/Other Brands
Firdapse / Zenas
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Amifampridine SerbTablet10 mgOralSerb Sa2022-06-01Not applicableEU flag
Amifampridine SerbTablet10 mgOralSerb Sa2022-06-01Not applicableEU flag
Amifampridine SerbTablet10 mgOralSerb Sa2022-06-01Not applicableEU flag
FirdapseTablet10 mg/1OralCatalyst Pharmaceuticals, Inc.2019-01-07Not applicableUS flag
FirdapseTablet10 mgOralSerb Sa2020-12-20Not applicableEU flag

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
  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. 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]
  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. 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]
  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]
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 Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentMuscle-specific tyrosine kinase (MuSK) myasthenia gravis1
3CompletedTreatmentCongenital Myasthenia (CM)1
3CompletedTreatmentGeneralized Myasthenia Gravis1
3CompletedTreatmentLambert Eaton Myasthenic Syndrome (LEMS)2
3CompletedTreatmentMultiple Sclerosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
TabletOral10 mg/1
TabletOral10 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10793893No2020-10-062034-04-07US flag
US11060128No2021-07-132032-06-29US flag
US11274332No2012-06-292032-06-29US flag
US11274331No2012-06-292032-06-29US flag
US11268128No2012-06-292032-06-29US flag
US10626088No2020-04-212037-02-25US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)229 ± 2EMA Assessment Report
water solubility freely soluble in water, and slightly soluble in solvents ethanol, methanol and acetic acidL43312
Predicted Properties
PropertyValueSource
Water Solubility159.0 mg/mLALOGPS
logP-0.48ALOGPS
logP-0.9Chemaxon
logS0.16ALOGPS
pKa (Strongest Basic)9.25Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area64.93 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity33.3 m3·mol-1Chemaxon
Polarizability10.94 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/MSsplash10-03di-0900000000-a65d033d7707deb33bec
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-1900000000-f2a291fa54d2db011cca
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-03di-6900000000-d3df2a20124c39e387a0
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-052f-9500000000-bb16b37df13e17a411ed
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0pvl-9000000000-207bbfeaaf87866b1376
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00kf-9000000000-ab621d26864bcd1d820c
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-115.4248579
predicted
DarkChem Lite v0.1.0
[M-H]-124.40396
predicted
DeepCCS 1.0 (2019)
[M+H]+115.1814579
predicted
DarkChem Lite v0.1.0
[M+H]+126.412796
predicted
DeepCCS 1.0 (2019)
[M+Na]+115.6991579
predicted
DarkChem Lite v0.1.0
[M+Na]+134.7598
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Potassium voltage-gated channel subfamily A member 1
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. [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]

Enzymes

Details1. Arylamine N-acetyltransferase 1
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
  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. [Article]
Details2. Arylamine N-acetyltransferase 2
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
  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. [Article]

Transporters

Details1. Solute carrier family 22 member 2
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
  1. FDA Approved Drug Products: RUZURGI (amifampridine) tablets [Link]

Drug created at October 17, 2016 21:29 / Updated at February 20, 2024 23:55