-
International Journal of Molecular... Feb 2023Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic... (Review)
Review
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.
Topics: Humans; Albuterol; Amifampridine; Cholinesterase Inhibitors; Mitochondrial Proteins; Mutation; Myasthenic Syndromes, Congenital; NAV1.4 Voltage-Gated Sodium Channel; Neuromuscular Junction; Receptors, Cholinergic; Symporters; Synaptic Transmission
PubMed: 36835142
DOI: 10.3390/ijms24043730 -
Australian Prescriber Oct 2022
Review
PubMed: 36382167
DOI: 10.18773/austprescr.2022.056 -
Clinical Therapeutics Jul 2017The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive...
PURPOSE
The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes.
METHODS
This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations.
FINDINGS
Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC and C were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC approximately 1.8-fold; C approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC from normal to severe RI. No new tolerability findings were observed.
IMPLICATIONS
A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.
Topics: 4-Aminopyridine; Acetylation; Adult; Aged; Amifampridine; Female; Humans; Kidney; Male; Middle Aged; Potassium Channel Blockers; Renal Insufficiency
PubMed: 28641995
DOI: 10.1016/j.clinthera.2017.05.353 -
Journal of Neurology Nov 2022Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration. SMN-enhancing therapies are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission could contribute to SMA phenotype. Amifampridine prolongs presynaptic NMJ terminal depolarization, enhancing neuromuscular transmission.
METHODS
SMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled crossover study. Ambulatory (walking unaided at least 30 m) SMA Type 3 patients, untreated with SMN-enhancing medications, entered a run-in phase where amifampridine was titrated up to an optimized stable dose. Patients achieving at least three points improvement in Hammersmith Functional Motor Score Expanded (HFMSE) were randomized to amifampridine or placebo, alternatively, in the 28-day double-blind crossover phase. Safety was evaluated by adverse events (AE) collection. Primary efficacy measure was the HFMSE change from randomization. Secondary outcomes included timed tests and quality of life assessment. Descriptive analyses and a mixed effects linear model were used for statistics.
RESULTS
From 14 January 2019, 13 patients, mean age 34.5 years (range 18-53), with 5/13 (38.5%) females, were included. No serious AE were reported. Transient paresthesia (33.3%) was the only amifampridine-related AE. Six patients for each treatment sequence were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (mean difference 0.792; 95% CI from 0.22 to 1.37; p = 0.0083), compared to placebo, but not in secondary outcomes.
DISCUSSION
SMA-001 study provided Class II evidence that amifampridine was safe and effective in treating ambulatory SMA type 3 patients.
CLINICAL TRIAL REGISTRATION
NCT03781479; EUDRACT 2017-004,600-22.
Topics: Amifampridine; Cross-Over Studies; Female; Humans; Male; Muscular Atrophy, Spinal; Quality of Life; Spinal Muscular Atrophies of Childhood
PubMed: 35763114
DOI: 10.1007/s00415-022-11231-7 -
Cureus Aug 2019Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune-mediated neurological disorder that manifests as muscle fatigue, diminished tendon reflexes, with symptoms of... (Review)
Review
Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune-mediated neurological disorder that manifests as muscle fatigue, diminished tendon reflexes, with symptoms of cholinergic overactivity. It can be associated with certain neoplastic conditions, the most common being small cell lung carcinoma (SCLC). The basic pathophysiology involved is antibody-mediated targeting of voltage-gated calcium channels (VGCC), which decreases the release of acetylcholine in the synaptic junction. Multiple treatment options have been introduced in the past and, recently, a new drug, amifampridine, has been approved by the Food and Drug Administration (FDA) for the treatment of weakness associated with these patients. We summarize this newly introduced drug with a brief description of other treatment options available.
PubMed: 31637147
DOI: 10.7759/cureus.5450 -
Journal of Clinical Neuromuscular... Mar 2019To assess tolerability and efficacy of amifampridine phosphate versus placebo for symptomatic treatment of Lambert-Eaton Myasthenic Syndrome (LEMS). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess tolerability and efficacy of amifampridine phosphate versus placebo for symptomatic treatment of Lambert-Eaton Myasthenic Syndrome (LEMS).
METHODS
This phase 3 randomized, double-blind, placebo-controlled withdrawal trial in 26 adults with LEMS compared efficacy of amifampridine phosphate versus placebo over a 4-day period. The primary endpoints were quantitative myasthenia gravis score (QMG) and subject global impression, and the secondary endpoint was Clinical Global Impression-Improvement. The exploratory endpoints were 3TUG (timed up and go) test and QMG limb domain score. All participants had been receiving amifampridine phosphate (30-80 mg/d divided into 3 or 4 doses daily) in an expanded access protocol and had been titrated to the optimal dose and frequency for at least 1 week before randomization into the current study. After completion of assessments after 4 days of double-blind treatment, patients had the option to return to open-label amifampridine phosphate. The efficacy endpoints were mean changes from baseline in the various evaluation parameters.
RESULTS
Amifampridine phosphate (n = 13) demonstrated significant benefit in QMG and subject global impression compared with placebo (n = 13) at 4 days. Other measures of efficacy, including Clinical Global Impression-Improvement, 3TUG, and QMG limb domain score also improved. The most common "adverse events" in the placebo group were muscle weakness (n = 5) and fatigue (n = 4), as expected from withdrawal of amifampridine phosphate, whereas only back pain (n = 1), pain in extremity (n = 1), and headache (n = 1) were reported in amifampridine phosphate group.
CONCLUSIONS
This phase 3 randomized, double-blind, placebo-controlled withdrawal trial in adults with LEMS provided class I evidence of efficacy of amifampridine phosphate as symptomatic treatment in LEMS.
Topics: Adult; Aged; Amifampridine; Double-Blind Method; Female; Humans; Lambert-Eaton Myasthenic Syndrome; Male; Middle Aged; Neural Conduction; Neuromuscular Agents; Severity of Illness Index; Treatment Outcome; United States
PubMed: 30801481
DOI: 10.1097/CND.0000000000000239 -
Clinical Therapeutics Jul 2015Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure.
METHODS
This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3-N-acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC0-∞, AUC0-t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC0-∞, AUC0-t, or Cmax between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use.
FINDINGS
Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed.
IMPLICATIONS
At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.
Topics: 4-Aminopyridine; Administration, Oral; Adult; Amifampridine; Area Under Curve; Biological Availability; Cross-Over Studies; Eating; Fasting; Female; Food-Drug Interactions; Half-Life; Healthy Volunteers; Humans; Male; Middle Aged; Phosphates; Therapeutic Equivalency; Young Adult
PubMed: 26101174
DOI: 10.1016/j.clinthera.2015.05.498 -
Pharmaceutics May 2023Amifampridine 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...
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 -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--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--acetylamifampridine to amifampridine (AUC/AUC) 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 (K) 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.
PubMed: 37242713
DOI: 10.3390/pharmaceutics15051471