Peringatan Keamanan

The approximate oral LD50 was >25mg/kg in rats and 100 mg/kg in mice.L50231 The approximate intravenous LD50 was 25 mg/kg in both rats and mice.L50231 Peritoneal and subcutaneous LD50 in mice were 20 mg/kg and 35 mg/kg, respectively.A33863 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 F272.

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 F272. 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 F272. 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 F272.

Amifampridine

DB11640

small molecule approved investigational

Deskripsi

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 A33863. 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 L3171. 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 L4819.

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 A33863. About 50-60% of the patients develop more rapidly progressive LEMS and small cell lung cancer, which influences the prognosis A33863. 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 A33863. 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 A33863. This leads to the reduction of the compound muscle action potential (CMAP) A33863. 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 A33863. 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 A33864. 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 F272. Slow acetylators were at higher risk for experiencing drug-associated adverse reactions, such as paresthesias, nausea, and headache F272.

Struktur Molekul 2D

Berat 109.132
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (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.[L36425]
Volume Distribusi 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.[L36425] After a 2 mg/kg infusion in rats, the volume of distribution at steady-state was 2.8 ± 0.7 L/kg.[A252822] 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 [F272]. Concentrations in tissues are generally similar to or greater than concentrations in plasma [F272].
Klirens (Clearance) Overall clearance of amifampridine is both metabolic and renal; it is primarily cleared from the plasma via metabolism by N-acetylation [F272]. 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.[L36425]

Absorpsi

Orally-administered amifampridine is rapidly absorbed in humans to reach the peak plasma concentrations within by 0.6 to 1.3 hours F272. 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 F272. Bioavailability is approximately 93-100% based on recoveries of unmetabolised amifampridine and a major 3-N-acetylated amifampridine metabolite in urine F272. Food consumption decreases amifampridine absorption and exposure with a decrease in the time to reach maximum concentrations (Tmax) A33865. It is approximated that food consumption lowers the Cmax on average by ~44% and lowers AUC by ~20%. based on geometric mean ratios F272. Systemic exposure to amifampridine is affected by the overall metabolic acetylation activity of NAT enzymes and NAT2 genotype A33881. 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 A33881, F272.

Metabolisme

Amifampridine is extensively metabolized by N-acetyltransferase 2 (NAT2) to 3-N-acetyl-amifampridine, which is considered an inactive metabolite.L43312

Rute Eliminasi

Following oral administration, more than 93% of total amifampridine is renally eliminated within 24 hours A33865. 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 F272.

Interaksi Makanan

1 Data
  • 1. Take with or without food.

Interaksi Obat

499 Data
Ivabradine Ivabradine may increase the QTc-prolonging activities of Amifampridine.
Dofetilide The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Dofetilide.
Citalopram The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Citalopram.
Anagrelide The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Anagrelide.
Disopyramide The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Disopyramide.
Clemastine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Clemastine.
Ibutilide The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Ibutilide.
Valproic acid The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Valproic acid.
Terfenadine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Terfenadine.
Grepafloxacin The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Grepafloxacin.
Sotalol The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Sotalol.
Erlotinib The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Erlotinib.
Toremifene The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Toremifene.
Cisapride The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Cisapride.
Imatinib The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Imatinib.
Astemizole The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Astemizole.
Thioridazine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Thioridazine.
Trovafloxacin The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Trovafloxacin.
Mifepristone The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Mifepristone.
Arsenic trioxide The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Arsenic trioxide.
Escitalopram The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Escitalopram.
Domperidone The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Domperidone.
Sparfloxacin The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Sparfloxacin.
Bepridil The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Bepridil.
Paliperidone The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Paliperidone.
Lithium cation The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Lithium cation.
Temafloxacin The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Temafloxacin.
Zuclopenthixol The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Zuclopenthixol.
Tetrabenazine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Tetrabenazine.
Dronedarone The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Dronedarone.
Nilotinib The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Nilotinib.
Iloperidone The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Iloperidone.
Vandetanib The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Vandetanib.
Romidepsin The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Romidepsin.
Asenapine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Asenapine.
Artemether The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Artemether.
Lumefantrine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Lumefantrine.
Vemurafenib The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Vemurafenib.
Eliglustat The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Eliglustat.
Ribociclib The risk or severity of QTc prolongation can be increased when Ribociclib is combined with Amifampridine.
Glasdegib The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Glasdegib.
Deutetrabenazine The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Deutetrabenazine.
Macimorelin The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Macimorelin.
Terodiline The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Terodiline.
Amiodarone The risk or severity of QTc prolongation can be increased when Amifampridine is combined with Amiodarone.
Leuprolide The risk or severity of QTc prolongation can be increased when Leuprolide is combined with Amifampridine.
Goserelin The risk or severity of QTc prolongation can be increased when Goserelin is combined with Amifampridine.
Erythromycin The risk or severity of QTc prolongation can be increased when Erythromycin is combined with Amifampridine.
Azithromycin The risk or severity of QTc prolongation can be increased when Azithromycin is combined with Amifampridine.
Moxifloxacin The risk or severity of QTc prolongation can be increased when Moxifloxacin is combined with Amifampridine.
Ranolazine The risk or severity of QTc prolongation can be increased when Ranolazine is combined with Amifampridine.
Sulfisoxazole The risk or severity of QTc prolongation can be increased when Sulfisoxazole is combined with Amifampridine.
Diltiazem The risk or severity of QTc prolongation can be increased when Diltiazem is combined with Amifampridine.
Nimodipine The risk or severity of QTc prolongation can be increased when Nimodipine is combined with Amifampridine.
Promazine The risk or severity of QTc prolongation can be increased when Promazine is combined with Amifampridine.
Prochlorperazine The risk or severity of QTc prolongation can be increased when Prochlorperazine is combined with Amifampridine.
Oxaliplatin The risk or severity of QTc prolongation can be increased when Oxaliplatin is combined with Amifampridine.
Ciprofloxacin The risk or severity of QTc prolongation can be increased when Ciprofloxacin is combined with Amifampridine.
Fluorouracil The risk or severity of QTc prolongation can be increased when Fluorouracil is combined with Amifampridine.
Perflutren The risk or severity of QTc prolongation can be increased when Perflutren is combined with Amifampridine.
Cinnarizine The risk or severity of QTc prolongation can be increased when Cinnarizine is combined with Amifampridine.
Atropine The risk or severity of QTc prolongation can be increased when Atropine is combined with Amifampridine.
Efavirenz The risk or severity of QTc prolongation can be increased when Efavirenz is combined with Amifampridine.
Adenosine The risk or severity of QTc prolongation can be increased when Adenosine is combined with Amifampridine.
Pentamidine The risk or severity of QTc prolongation can be increased when Pentamidine is combined with Amifampridine.
Gadobenic acid The risk or severity of QTc prolongation can be increased when Gadobenic acid is combined with Amifampridine.
Carbinoxamine The risk or severity of QTc prolongation can be increased when Carbinoxamine is combined with Amifampridine.
Dolasetron The risk or severity of QTc prolongation can be increased when Dolasetron is combined with Amifampridine.
Roxithromycin The risk or severity of QTc prolongation can be increased when Roxithromycin is combined with Amifampridine.
Cinoxacin The risk or severity of QTc prolongation can be increased when Cinoxacin is combined with Amifampridine.
Loperamide The risk or severity of QTc prolongation can be increased when Loperamide is combined with Amifampridine.
Granisetron The risk or severity of QTc prolongation can be increased when Granisetron is combined with Amifampridine.
Ondansetron The risk or severity of QTc prolongation can be increased when Ondansetron is combined with Amifampridine.
Levosimendan The risk or severity of QTc prolongation can be increased when Levosimendan is combined with Amifampridine.
Mesoridazine The risk or severity of QTc prolongation can be increased when Mesoridazine is combined with Amifampridine.
Desloratadine The risk or severity of QTc prolongation can be increased when Desloratadine is combined with Amifampridine.
Telithromycin The risk or severity of QTc prolongation can be increased when Telithromycin is combined with Amifampridine.
Lomefloxacin The risk or severity of QTc prolongation can be increased when Lomefloxacin is combined with Amifampridine.
Dimenhydrinate The risk or severity of QTc prolongation can be increased when Dimenhydrinate is combined with Amifampridine.
Primaquine The risk or severity of QTc prolongation can be increased when Primaquine is combined with Amifampridine.
Papaverine The risk or severity of QTc prolongation can be increased when Papaverine is combined with Amifampridine.
Chlorpheniramine The risk or severity of QTc prolongation can be increased when Chlorpheniramine is combined with Amifampridine.
Nifedipine The risk or severity of QTc prolongation can be increased when Nifedipine is combined with Amifampridine.
Levofloxacin The risk or severity of QTc prolongation can be increased when Levofloxacin is combined with Amifampridine.
Gemifloxacin The risk or severity of QTc prolongation can be increased when Gemifloxacin is combined with Amifampridine.
Ofloxacin The risk or severity of QTc prolongation can be increased when Ofloxacin is combined with Amifampridine.
Propafenone The risk or severity of QTc prolongation can be increased when Propafenone is combined with Amifampridine.
Flecainide The risk or severity of QTc prolongation can be increased when Flecainide is combined with Amifampridine.
Clarithromycin The risk or severity of QTc prolongation can be increased when Clarithromycin is combined with Amifampridine.
Levacetylmethadol The risk or severity of QTc prolongation can be increased when Levacetylmethadol is combined with Amifampridine.
Saquinavir The risk or severity of QTc prolongation can be increased when Saquinavir is combined with Amifampridine.
Mibefradil The risk or severity of QTc prolongation can be increased when Mibefradil is combined with Amifampridine.
Probucol The risk or severity of QTc prolongation can be increased when Probucol is combined with Amifampridine.
Aceprometazine The risk or severity of QTc prolongation can be increased when Aceprometazine is combined with Amifampridine.
Terlipressin The risk or severity of QTc prolongation can be increased when Terlipressin is combined with Amifampridine.
Prenylamine The risk or severity of QTc prolongation can be increased when Prenylamine is combined with Amifampridine.
Fluspirilene The risk or severity of QTc prolongation can be increased when Fluspirilene is combined with Amifampridine.
Azimilide The risk or severity of QTc prolongation can be increased when Azimilide is combined with Amifampridine.
Pracinostat The risk or severity of QTc prolongation can be increased when Pracinostat is combined with Amifampridine.
Technetium Tc-99m ciprofloxacin The risk or severity of QTc prolongation can be increased when Technetium Tc-99m ciprofloxacin is combined with Amifampridine.

Target Protein

Potassium voltage-gated channel subfamily A member 1 KCNA1

Referensi & Sumber

Artikel (PubMed)
  • PMID: 21822385
    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.
  • PMID: 26852139
    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.
  • PMID: 26101174
    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.
  • PMID: 28641995
    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.
  • PMID: 31419315
    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.

Contoh Produk & Brand

Produk: 8 • International brands: 2
Produk
  • Amifampridine Serb
    Tablet • 10 mg • Oral • EU • Approved
  • Amifampridine Serb
    Tablet • 10 mg • Oral • EU • Approved
  • Amifampridine Serb
    Tablet • 10 mg • Oral • EU • Approved
  • Firdapse
    Tablet • 10 mg • Oral • Canada • Approved
  • Firdapse
    Tablet • 10 mg/1 • Oral • US • Approved
  • Firdapse
    Tablet • 10 mg • Oral • EU • Approved
  • Ruzurgi
    Tablet • 10 mg • Oral • Canada • Approved
  • Ruzurgi
    Tablet • 10 mg/1 • Oral • US • Approved
International Brands
  • Firdapse
  • Zenas

Sekuens Gen/Protein (FASTA)

Sekuens dimuat saat dibutuhkan agar halaman tetap ringan.
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