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Impact of extended-release dalfampridine on walking ability in patients with multiple sclerosis

By Keith C Hayes

Abstract

Dalfampridine extended release (ER) 10 mg is an oral tablet form of the potassium (K+) channel-blocking compounded dalfampridine, also known as fampridine, and chemically 4-aminopyridine or 4-AP, which received regulatory approval in the United States for the treatment of walking in patients with multiple sclerosis (MS) in January 2010. Two pivotal Phase 3 clinical trials demonstrated significant improvements in walking in patients with the four primary forms of MS following administration of dalfampridine ER tablets 10 mg twice daily. The drug is thought to act by restoring conduction in focally demyelinated axons and by enhancing neurotransmission, thereby leading to improved neurological function. This review describes how dalfampridine represents a new pharmacotherapeutic approach to the clinical management of mobility impairment. It describes the mechanism of action and chemistry of dalfampridine ER, its pharmacokinetics, tolerability, and side effects, and the outcomes of multicenter trials showing its efficacy in improving walking speed. Clinician and patient global assessments, as well as patient self-assessment of the impact of MS on their gait disability, confirm clinically relevant benefit from the therapy. Patients tolerate the drug well and their improvement in terms of household and community ambulation, inferred from analysis of pooled data from several studies, is likely to translate into benefits in the performance of instrumental activities of daily living and a reduction in the neuropsychiatric burden of disease

Topics: Review
Publisher: Dove Medical Press
OAI identifier: oai:pubmedcentral.nih.gov:3090287
Provided by: PubMed Central

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Citations

  1. (1987). 4-Aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol.
  2. (1991). 4-Aminopyridine in multiple sclerosis: Prolonged administration.
  3. (1994). 4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety. Arch Neurol.
  4. (1993). 4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study.
  5. (1985). 4-aminopyridine leads to restoration of conduction in demyelinated rat sciatic nerve. Brain Res.
  6. 4-aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis.
  7. (1981). 4-aminopyridine; analysis of the substance and a method for the preparation of a solution for injection in man. Pharm Acta Helv.
  8. 4-Aminopyridine: new life for an old drug.
  9. (2010). 4-Aminopyridine: new life for an old drug. Ann Neurol.
  10. A comprehensive assessment of the cost of multiple sclerosis in the United states.
  11. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.
  12. and the pathophysiology of multiple sclerosis.
  13. (2009). Assessment of the cardiac safety of fampridine-SR sustained-release tablets through a thorough QT/QTc evaluation at therapeutic and subtherapeutic doses in healthy individuals. Expert Opin Inv Drugs.
  14. (1996). Atypical presentation of 4-aminopyridine overdose. Ann Emerg Med.
  15. (2011). Biogen Idec website. www.biogenidec.com. Accessed
  16. (1994). Characterization of 4-aminopyridine in overdose.
  17. (2010). Cognitive impairment in multiple sclerosis is associated to different patterns of gray matter atrophy according to clinical phenotype. Hum Brain Mapp.
  18. (1977). Conduction in myelinated, unmyelinated, and demyelinated fibers. Arch Neurol.
  19. Contribution of impaired mobility to patient burden in multiple sclerosis. Curr Med Res Opin.
  20. Correlating brain atrophy with cognitive dysfunction, mood disturbances, and personality disorder in multiple sclerosis.
  21. Dalfampridine extended release in multiple sclerosis.
  22. Dalfampridine in multiple sclerosis. Drugs Today (Barc).
  23. (2001). Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension. Mult Scler.
  24. Effects of 4-aminopyiridine on normal and demyelinated mammalian nerve fibres.
  25. (1978). Effects of 4-aminopyridine on neuromuscular transmission. Brain Res.
  26. (1982). Effects of 4-aminopyridine on synaptic transmission in the cat spinal cord. Brain Res.
  27. (2007). Endocr Metab Immune Disord Drug Targets.
  28. Fampridine for MS responders: Clinically relevant or hypothesis generating?
  29. Fampridine MS-F202 Study Group. Dose comparison trial of sustained-release fampridine in multiple sclerosis.
  30. (2007). Fampridine-SR for multiple sclerosis and spinal cord injury. Exp Rev Neurother.
  31. (2007). Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo controlled, dose ranging study. Mult Scler.
  32. (2011). Food and Drug Administration: Medication Guide for AmpyraTM (dalfampridine) Extended Release Tablets.
  33. (2011). Food and Drug Administration: Prescribing Information for AmpyraTM (dalfampridine) extended release tablets. www.accessdata.fda.gov/drugsatfda_docs/label/.../022250s000 lbl.pdf. Accessed
  34. (2011). Food and Drug Administration: Risk Evaluation and Mitigation Strategy (REMS) for Ampyra (Dalfampridine) 10 mg tablets. http://www.accessdata.fda.gov/drugsatfda_docs/ label/2010/022250s000REMS.pdf. Accessed
  35. Functional MR imaging correlates of neuropsychological impairment in primary-progressive multiple sclerosis.
  36. Immunotherapeutic approaches in MS: update on pathophysiology and emerging agents
  37. Impact of loss of mobility on instrumental activities of daily living and socioeconomic status in patients with MS. Curr Med Res Opin.
  38. (2010). Impact of mobility impairment on the burden of caregiving in individuals with multiple sclerosis. Expert Rev Pharmacoeconomics Outcome Res.
  39. (2008). Key findings from two new multiple sclerosis surveys [internet].
  40. Measuring the impact of MS on walking ability:
  41. (2010). Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol.
  42. Multiple sclerosis – candidate mechanisms underlying CNS atrophy. Trends Neuroscience.
  43. (1983). Multiple sclerosis and mobility restriction. Arch Phys Med Rehabil.
  44. Multiple sclerosis and mobilityrelated technology: sytematic review of literature.
  45. Multiple sclerosis.
  46. (2006). Neuropsychiatric manifestations of multiple sclerosis. Neurol Res.
  47. New approaches to the management of multiple sclerosis. Drug Des Dev Ther.
  48. On the interaction of disability and aging: Accelerated degradation models and their influence of projections of future care needs and costs for personal injury litigation. Disabil Rehabil.
  49. Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis.
  50. Overcoming conduction failure in de-myelinated nerve fibres by prolonging action potentials.
  51. Pharmacokinetics and tolerability of single escalating doses of fampridine sustained-release tablets in patients with multiple sclerosis: a phase 1–11, open-label trial. Clin Ther.
  52. (1987). Physiological effects of 4-aminopyridine on demyelinated mammalian motor and sensory fibers. Ann Neurol.
  53. (2006). Potassium channel blockers in multiple sclerosis: Neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther.
  54. (1997). Quantitative assessment of sustained release 4-aminopyridine for symptomatic treatment of multiple sclerosis.
  55. (2009). Severe accidental overdose of 4-aminopyridine due to compounding pharmacy error. J Emerg Med.
  56. Single-dose pharmacokinetics of sustained-release fampridine (Fampridine-SR) in healthy volunteers and adults with renal impairment.
  57. (2009). Steady-state pharmacokinetics and tolerability of orally administered fampridine sustained-release 10-mg tablets in patients with multiple sclerosis; a 2-week, open-label, follow-up study. Clin Ther.
  58. (2009). Sustained release oral fampridine in the treatment of multiple sclerosis. Expert Opin Pharmacother.
  59. (2009). Sustained-release fampridine for multiple sclerosis. Expert Opin Investig Drugs.
  60. Sustained-release fampridine for symptomatic treatment of multiple sclerosis.
  61. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
  62. The cost of dichotomizing continuous variables.
  63. (1992). The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Ann Neurol.
  64. The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.
  65. (1994). The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial.
  66. The effects of experimental demyelination on conduction in the central nervous system.
  67. The neuropsychiatry of multiple sclerosis: a review of recent developments.
  68. The neuropsychiatry of multiple sclerosis: focus on disorders of mood, affect and behaviour. Int Rev Psychiatry.
  69. The pharmacokinetics and tolerability of a slow-release formulation of 4-aminopyridine in multiple sclerosis patients. Neurology. 1995;45(Suppl 4):A351.