Amifampridine phosphateProduct ingredient for Amifampridine

Name
Amifampridine phosphate
Drug Entry
Amifampridine

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 10. Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache 10.

Accession Number
DBSALT002818
Structure
Synonyms
3,4-DAPP / DAPP
UNII
8HF8FIN815
CAS Number
446254-47-3
Weight
Average: 207.126
Monoisotopic: 207.040892812
Chemical Formula
C5H10N3O4P
InChI Key
KAICRBBQCRKMPO-UHFFFAOYSA-N
InChI
InChI=1S/C5H7N3.H3O4P/c6-4-1-2-8-3-5(4)7;1-5(2,3)4/h1-3H,7H2,(H2,6,8);(H3,1,2,3,4)
IUPAC Name
phosphoric acid; pyridine-3,4-diamine
SMILES
OP(O)(O)=O.NC1=CC=NC=C1N
ChemSpider
8096351
ChEMBL
CHEMBL3301611
Wikipedia
Amifampridine
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