Amifampridine 10mg tablets

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular disorder caused by pathogenic autoantibodies directed against voltage-gated calcium channels present on the presynaptic nerve terminal. For LEMS patients refractory to initial symptomatic treatment with amifampridine, immunomodulatory therapy with intravenous immunoglobulin (IVIG) is often utilized. However, in the authors' review of literature, the utility of subcutaneous immunoglobulin (SCIG) in the treatment of LEMS has been scarcely reported. Here, we present a unique case of non-paraneoplastic LEMS managed with SCIG with excellent clinical response and improvement on electromyography. SCIG therapy may be a reasonable alternative for patients with LEMS who do not tolerate the intravenous formulation.

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Highlight: LEMS is a rare neurological disease with fluctuating symptoms Delays and misdiagnosis of LEMS disease often occur The two main pathophysiologies of LEMS are autoimmune and paraneoplastic. ABSTRACT A rare condition known as Lambert-Eaton myasthenic syndrome (LEMS) affects the neuromuscular junctions, which are the connections between muscles and nerves. Tumor-associated or autoimmune causes trigger this condition. This mechanism depends on the presence of antibodies that directly attach to voltage-gated calcium channels located on the presynaptic nerve terminals. LEMS disease is divided into non-paraneoplastic or non-tumor LEMS (NT-LEMS) and paraneoplastic LEMS (P-LEMS). NT-LEMS is believed to be caused by an autoimmune process. On the other hand, P-LEMS has an underlying tumor, and LEMS symptoms are paraneoplastic manifestations of the tumor. Clinical signs of LEMS include proximal muscle weakness, autonomic dysfunction, and decreased deep tendon reflexes. The predominant sign of LEMS is weakness of the lower extremities. The defining characteristic of LEMS is a weakness that spreads from caudal to cranial, causing oculobulbar manifestations, and from proximal to distal, potentially involving the feet and hands. The diagnosis of LEMS depends on clinical, electromyographic, and serological findings of anti-VGCC antibodies. Therefore, comprehensive oncologic screening and monitoring should promptly follow a diagnosis of LEMS. The standard approach to treating LEMS symptoms is administering drugs that improve neurotransmission, such as potassium channel blockers and amifampridine. In refractory cases, immunosuppressants or immunomodulator agents, such as a combination of prednisone and azathioprine, are used. If a tumor is detected, oncological therapy should be a priority.

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Amifampridine is a drug used for the treatment of Lambert–Eaton myasthenic syndrome (LEMS) and was approved by the Food and Drug Administration (FDA) of the United States (US) in 2018. It is mainly metabolized by N-acetyltransferase 2 (NAT2); however, investigations of NAT2-mediated drug interactions with amifampridine have rarely been reported. In this study, we investigated the effects of acetaminophen, a NAT2 inhibitor, on the pharmacokinetics of amifampridine using in vitro and in vivo systems. Acetaminophen strongly inhibits the formation of 3-N-acetylamifmapridine from amifampridine in the rat liver S9 fraction in a mixed inhibitory manner. When rats were pretreated with acetaminophen (100 mg/kg), the systemic exposure to amifampridine significantly increased and the ratio of the area under the plasma concentration–time curve for 3-N-acetylamifampridine to amifampridine (AUCm/AUCp) decreased, likely due to the inhibition of NAT2 by acetaminophen. The urinary excretion and the amount of amifampridine distributed to the tissues also increased after acetaminophen administration, whereas the renal clearance and tissue partition coefficient (Kp) values in most tissues remained unchanged. Collectively, co-administration of acetaminophen with amifampridine may lead to relevant drug interactions; thus, care should be taken during co-administration.

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In 1983, the first successful trial of 3,4-diaminopyridine (3,4-DAP) in Lambert-Eaton myasthenic syndrome (LEMS) was reported. Efficacy of amifampridine (3,4-DAP and 3,4-diaminopyridine phosphate [3,4-DAPP]) for symptomatic treatment in LEMS was proven by seven randomized studies in 3,4-DAP and two randomized studies in 3,4-DAPP. US Food Drug Administration approved 3,4-DAPP usage for adult LEMS in 2018 and for pediatric LEMS in 2022. Nineteen pediatric LEMS cases were identified in the literature. Compared with adult LEMS, the rate of malignancy is low as expected and the rate of dysautonomia is also low in pediatric LEMS. Unexpected finding is two cases of pediatric LEMS following antecedent infection. Amifampridine can be safely used as long the daily dose is less than 80 mg a day for adult LEMS patients and less than 30 mg a day for pediatric LEMS patients. Amifampridines can be supplemented with a liberal amount of pyridostigmine for long term usage. Amifampridine was used as symptomatic treatment in eight (42%) of 19 pediatric LEMS patients: 3,4-DAP in six and 3,4-DAPP in two patients. The most common practice of 3,4-DAP was a combination with pyridostigmine in four patients. With 3,4-DAP, normal activity was reported in 3 cases and mild to moderate-improvement in other 3 cases. In two patients with 3,4-DAPP, significant improvement in one and no improvement in one. Amifampridines are proven to be effective and safe drugs for the symptomatic treatment without serious side reaction in adults as well as in children as long as the dosage is properly adhered.

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Introduction: Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction, with limited large-scale epidemiological data. In this study, we aimed to determine the epidemiological profile of LEMS in Türkiye, and to assess associated malignancies, mortality, and prescription rates of pyridostigmine and amifampridine. Methods: We identified LEMS cases through a retrospective review of clinical records for individuals with a G73.1 code entry in the national healthcare database between 2015 and 2024. Confirmed cases were classified as autoimmune (A-LEMS) or paraneoplastic (P-LEMS). Demographic, clinical, and prescription data were analyzed, and incidence and prevalence rates were calculated using official census data. Results: A total of 159 LEMS cases were confirmed. The median age at diagnosis was 60 years, and 55.3% of the patients were female. P-LEMS accounted for 59.7% of cases, with small cell lung cancer (SCLC) present in 55.8% of these. Annual incidence of LEMS ranged from 0.09 to 0.30 per million, and the overall 2024 prevalence was 1.11 per million. A-LEMS had a higher prevalence than P-LEMS in 2024, likely due to its lower mortality (23.4% vs. 58.9%). P-LEMS was more common in older males and predominantly associated with SCLC. Pyridostigmine was prescribed to 65.4% of patients, and amifampridine to 24.5%, with both treatments more frequently used in A-LEMS. Discussion: This is the first nationwide epidemiological study of LEMS in Türkiye, revealing lower incidence and prevalence rates than in other countries. This study provides valuable large-scale epidemiological data, enriching the global understanding of this rare disorder.

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The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human N-acetyltransferase 2 (NAT2) gene. NAT2 metabolizes several clinically used drugs including isoniazid, hydralazine, amifampridine, procainamide, and sulfonamides such as dapsone, and also some highly carcinogenic arylamines. Systematic nomenclature describing NAT2 variation is essential for pharmacogenetic testing, genotype interpretation, and translation to phenotype in research and clinical settings. This GeneFocus provides an overview of NAT2 variation and describes important changes to its star allele-based nomenclature that were made as it was transitioned to PharmVar in March 2024. We also highlight and discuss challenges regarding the characterization of allelic variation and determination of allele frequencies across world populations. The "new" NAT2 PharmVar nomenclature is utilized by ClinPGx (formerly PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

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