Neuropharmacology & Neurotherapeutics
Gene therapy of cerebrovascular disease
Aug. 24, 2021
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Dalfampridine is an extended-release formulation of fampridine (4-aminopyridine). 4-aminopyridine has a restricted use as an extremely effective bird poison sold under the brand name Avitrol, which is highly toxic to all mammals, including humans, if dosages are exceeded. Compounded forms of the active agent of sustained-release fampridine have been used in clinical practice for many years and shown to improve walking ability in patients with multiple sclerosis. Clinical trials have now been completed that demonstrate effectiveness of the drug with statistical significance and clinically meaningful end points (14). In 2010, the FDA approved dalfampridine (Ampyra™), which is the first oral therapy for multiple sclerosis. Approval of dalfampridine will enable patients to obtain a consistent exact dosage in a guaranteed time-released formula and avoids the risk of getting an uncertain preparation from a compounding pharmacy with possible adverse effects. A life-threatening accidental overdose of fampridine due to a compounding pharmacy error has been reported (27).
Pharmacodynamics. The exact mode of action is not known, but dalfampridine is a blocker of voltage-gated potassium channels that can increase action potential duration and amplitude, leading to improved conduction in demyelinated nerve fibers and to increased neurotransmitter release at synaptic endings (02). Therapeutic plasma concentrations associated with improved walking are in the range of 0.25 µM, but no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range (08). Findings of 1 study challenge the conventional view that fampridine facilitates synaptic and neuromuscular transmission by blocking voltage-gated potassium channels and suggests instead that fampridine can directly target presynaptic high voltage-activated calcium channels to potentiate neurotransmitter release independent of potassium channels (34).
Pharmacokinetics. Dalfampridine, a sustained-release oral preparation of fampridine, is rapidly absorbed but absolute bioavailability has not been assessed. The extended-release tablet has a relative bioavailability of 96% when compared to an aqueous oral solution, with delayed absorption giving a slower rise to a lower maximum plasma concentration with no effect on the extent of absorption. Peak concentrations are reached 3 to 4 hours post-administration. Dalfampridine was nearly completely and rapidly eliminated as unchanged drug via urinary excretion in trials on healthy volunteers, suggesting that it is unlikely to undergo substantial metabolic transformation (04). The mean terminal disposition half-life is 6.4 hours in healthy individuals. Pharmacokinetics of dalfampridine has been studied in clinical trials of patients with multiple sclerosis in which the dose was titrated (33). Significant findings of this study were:
(1) The steady-state pharmacokinetic profile of fampridine sustained-release 20 mg twice daily administered for 2 weeks appeared to support the use of twice daily dosing in this population.
(2) This dosage was generally well tolerated.
A phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study of sustained-release fampridine in multiple sclerosis patients showed significantly more consistent responders, as judged by improvement in walking, compared to the placebo group (10).
A randomized, multicenter, double-blind, controlled, phase 3 trial assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis (12). Fampridine improved walking ability, which was a clinically meaningful therapeutic benefit. Another phase 3 trial was designed to confirm efficacy and further define safety and pharmacodynamics of fampridine (11). Dalfampridine produced clinically meaningful improvement in walking ability in a subset of patients with multiple sclerosis with the effect maintained between doses. A review of clinical trials concluded that dalfampridine improved walking speed in approximately one third of multiple sclerosis patients (21).
Results of ENABLE, a 48-week, open-label, phase 4 study of dalfampridine, showed improvement of patient-perceived physical and psychological health impact of multiple sclerosis with walking impairment in a real-life setting (17). In a randomized, double-blind placebo-controlled crossover study, dalfampridine did not show an effect on accelerometer-measured ambulatory activity in persons with multiple sclerosis-related walking difficulty (05). A randomized clinical trial has shown that dalfampridine benefits timed ambulation but not cognition (26).
A substudy of a randomized, double-blind, placebo-controlled trial originally designed to explore the effect of dalfampridine on the speed of information processing in patients with multiple sclerosis (EU Clinical Trials Register number 2013-002558-64) showed that dalfampridine improved static balance (23).
A meta-analysis of controlled clinical trials has shown that dalfampridine is effective for improving walking ability, finger dexterity, and cognitive function in patients with multiple sclerosis (35).
Dalfampridine is indicated as a treatment to improve walking in patients with multiple sclerosis.
• A phase 2 trial of dalfampridine in chronic spinal cord injury showed some improvement of spasticity. No further development has been reported.
• Episodic ataxia type 2 (07)
• A double-blind, placebo-controlled, randomized clinical trial of dalfampridine in patients with chronic stroke deficits showed effect on sensorimotor function of the lower extremities with an improvement in walking speed (28).
• Pharmacological treatment option for nystagmus (30)
• Dalfampridine has been shown to reduce spasticity and improve hand dexterity in patients with hereditary spastic paraparesis who complain of walking impairments (32).
• Nonarteritic anterior ischemic optic neuropathy (19)
• A phase 1, double-blind, placebo-controlled clinical trial showed that dalfampridine is not effective in adult cerebral palsy (01).
Dalfampridine is contraindicated in patients with a prior history of a seizure disorder. Dalfampridine is contraindicated in people with severe renal impairment (29).
Clinical trials show that a subgroup of patients treated with dalfampridine experience an improvement in walking ability as demonstrated by an increase in walking speed, which is sustained for at least 14 weeks. Further use in clinical practice may help to determine the extent to which the drug may impact other functions and may also provide hints as to which patients are most likely to respond positively to the therapy. Extensions of the 2 phase 3 trials showed that consistent improvements in walking speed were sustained above baseline for up to 2.5 years of dalfampridine extended release treatment (06). In managed care populations, improved walking by dalfampridine treatment could potentially help contain some of the direct and indirect costs associated with care of multiple sclerosis (18). A study found that prior authorization of dalfampridine in accordance with FDA-approved labeling, by selecting appropriate subjects for initial therapy, improved safety and minimized dalfampridine costs (09). An open-label observational study showed that improvement in maximum walking distance as well as in motor and cognitive fatigue persisted beyond 1 year (24). An observational study has shown that dalfampridine may improve cognition and fatigue in persons with multiple sclerosis (31). Another study of dalfampridine in multiple sclerosis showed beneficial effects of dalfampridine on cognition, depression, and fatigue, which were not limited to patients who responded to dalfampridine with improved mobility measures (16).
Combination of physical therapy with extended-release dalfampridine therapy improves gait speed more than the use of the drug alone (22). Results of a review of the medical records of patients with multiple sclerosis suggests that a timed 25-foot walk (T25FW) alone might not be enough for assessing improvement and that adding patient-reported ambulation inventory can improve the evaluation of therapeutic response (15).
Dalfampridine is administered orally as 10 mg tablets twice a day.
Creatinine clearance should be calculated prior to initiating treatment with dalfampridine because impairment of renal function can lead to a rise of plasma levels of the drug. The approved 10 mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. The pharmacokinetics of dalfampridine extended release 7.5 mg twice daily in subjects with mild renal impairment is comparable to 10 mg twice daily in patients with multiple sclerosis who had normal renal function (25).
Pediatric. Safety and effectiveness of dalfampridine in patients younger than 18 years of age have not been established.
Geriatric. Dalfampridine clearance decreases slightly with increasing age, but not sufficiently to necessitate a modification of dose with age.
Pregnancy. Oral administration of dalfampridine in studies on rats did not cause any adverse effects on fertility. There are no adequate and well-controlled studies of dalfampridine in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at doses similar to the maximum recommended human dose of 20 mg/day. Dalfampridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Voltage-gated potassium channels regulate uterine muscle contractibility and blocking of these channels could affect uterine contraction. The effect of dalfampridine on labor and delivery in humans is unknown. It is not known whether dalfampridine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dalfampridine, a decision should be made whether to discontinue nursing or to discontinue the drug.
Anesthesia. There is no published information available for the interaction of fampridine with anesthetic agents.
Because dalfampridine is not a substrate or an inhibitor for the P-glycoprotein transporter, its pharmacokinetics are unlikely to be affected by drugs that inhibit the P-glycoprotein transporter, and it is not likely to interact with drugs that are substrates of the P-glycoprotein transporter. Dalfampridine kinetics is not affected by coadministration of subcutaneous injections of interferon beta 1b.
Fampridine, particularly in higher doses, ie, 15 mg twice daily, can cause seizures in some patients, but the incidence is lower in those receiving a 10 mg dose. However, dalfampridine may increase the risk of seizure, particularly in patients with renal impairment. Besides seizures, de novo convulsive status epilepticus has been reported as complication of dalfampridine in patients with multiple sclerosis and required discontinuation of the drug (20).
Treatment-related adverse events associated with the use of dalfampridine in clinical trials include dizziness, insomnia, nausea, and paresthesias. The risk of seizures in patients on dalfampridine therapy with no prior seizure history may not be greater than the risk already present in the multiple sclerosis population (13).
Dalfampridine may aggravate preexisting trigeminal neuralgia associated with multiple sclerosis (03).
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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Neuropharmacology & Neurotherapeutics
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Classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consists of a symmetrical proximal and distal weakness with variable sensory symptoms that exhibits either a relapsing, stepwise progressive or steadily progressive course. Aside from limb weakness, patients often have fatigue, numbness, tingling, or tight sensation in their extremities. Painful symptoms include burning, aching, tenderness, or jabbing feelings.
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Susac syndrome is typically a triad of encephalopathy, retinopathy, and hearing loss, but may have an atypical presentation. Most patients do not have the clinical triad at the onset of symptoms, but rather recurrences of one or more of the components of the triad. The syndrome is self-limiting and may go on for years, with fluctuations in its course.
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Neuropharmacology & Neurotherapeutics
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Neuropharmacology & Neurotherapeutics
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