A phase 3 trial of extended release oral dalfampridine in multiple sclerosis

Goodman, Andrew; Brown, Theodore R.; Edwards, Keith R.; Krupp, Lauren; Schapiro, Randall T.; Cohen, Ron; Marinucci, Lawrence N; Blight, Andrew R.

doi:10.1002/ana.22240

Cited by 338 publications

(383 citation statements)

References 20 publications

(42 reference statements)

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“…In the two phase III clinical trials, a treatment with 10 mg of dalfampridine twice daily improved the walking ability measured by the timed 25 Foot Walk test (T25FW) in responders by about 25%. Responders accounted for 35–43% of the study population (Goodman et al., 2009, 2010). Nonresponders did not benefit from dalfampridine treatment.…”

Section: Introductionmentioning

confidence: 99%

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Dalfampridine effects on cognition, fatigue, and dexterity

et al. 2016

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ObjectivesDalfampridine exerts beneficial effects on walking ability in a subgroup of patients with multiple sclerosis (MS). These patients are termed “responders”. Here, we investigated whether the responder status with respect to mobility measures would determine whether dalfampridine treatment exerts a beneficial effect on other MS symptoms. We therefore assessed walking ability, upper limb function, cognition, fatigue, visual evoked potentials (VEPs), depression, and quality of life in patients before and after dalfampridine treatment.MethodsPatients with MS and impaired mobility were recruited. Maximal walking distance, timed 25 Foot Walk, nine hole peg test, paced auditory serial addition test (PASAT), fatigue severity scale (FSS), VEPs, Beck Depression Inventory (BDI), EuroQol five dimensional questionnaire, and quality of life visual analogue scale were determined before and after 12–14 days of dalfampridine treatment. Repeated measures analysis of variance was applied to determine the effect of dalfampridine treatment.ResultsOf the 34 patients who completed the study, 22 patients were responders and 12 patients nonresponders, according to their performance in mobility measures. Treatment effects for the entire patient cohort were observed for PASAT (p = .029) and BDI (p = .032). Belonging to the responder cohort did not predict the response to treatment in these tests. For the FSS, response to dalfampridine treatment was dependent on the responder status (p = .001) while no effects in the total patient cohort were observed (p = .680). Other neurological functions remained unaltered. For VEP latencies, no significant improvements were detected.ConclusionIn this study, we observed beneficial effects of dalfampridine on cognition, depression, and fatigue. These effects were not limited to patients who responded to dalfampridine with improved mobility measures. These findings underscore the need to assess the beneficial effects of dalfampridine on neurological deficits in MS patients in additional randomized clinical trials.

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Section: Introductionmentioning

confidence: 99%

“…The most frequent adverse events were urinary tract infections, insomnia, dizziness, nausea, and headache. Furthermore, dalfampridine might increase the risk of seizure (Goodman et al., 2009, 2010). …”

Section: Introductionmentioning

confidence: 99%

Dalfampridine effects on cognition, fatigue, and dexterity

et al. 2016

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“…This formulation is known as prolonged-, modified, or sustained release fampridine in some countries outside of the USA. Approval was based on two phase 3 clinical trials that showed an approximate mean 25% increase in walking speed among the 35–43% of patients who responded to treatment with dalfampridine-ER2,3.…”

Section: Introductionmentioning

confidence: 99%

Identification of metabolites of dalfampridine (4-aminopyridine) in human subjects and reaction phenotyping of relevant cytochrome P450 pathways

Caggiano

Blight

2013

Journal of Drug Assessment

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ObjectivesAn extended release formulation of dalfampridine (4-aminopyridine; 4-AP), a potassium channel blocker is available in the USA to improve walking in patients with multiple sclerosis. This study investigated the human metabolites of 4-AP and the cytochrome P450 (CYP450) pathways responsible for 4-AP metabolism.MethodsMetabolites were identified, using thin layer chromatography, high performance liquid chromatography, and gas chromatography/mass spectroscopy, in plasma and urine samples obtained during an excretion balance study of four subjects who were administered a single oral 15-mg dose of 14C-4-AP. Samples were compared with authentic standards of 4-AP, 2-hydroxy-4AP, 3-hydroxy-4AP, and 4-AP-N-oxide. Reaction phenotyping was performed in vitro using human liver microsomes and recombinant CYP450 enzymes with incubation in the presence of direct and time-dependent inhibitors to determine the CYP450 pathways involved in metabolite formation.ResultsWhile most (∼70%) of the radioactivity detected in plasma at each time point corresponded to unchanged 4-AP, two major metabolites were recovered. One metabolite co-localized with the authentic reference standard of 3-hydroxy-4-AP, and the other metabolite was identified as the sulfate conjugate of 3-hydroxy-4-AP. Two minor components were observed, one accounting for 2% of radioactivity and the other below the level of quantitation. Reaction phenotyping showed moderate correlations for conversion of 4-AP to 3-hydroxy-4AP with both CYP2E1 (r = 0.596; p < 0.001) and CYP2C8 (r = 0.608; p < 0.001). Use of a CYP2E1 metabolism-dependent inhibitor inhibited formation of 3-hydroxy-4-AP with and without pre-incubation (higher inhibition with pre-incubation), further supporting the likelihood of CYP2E1 as a metabolic pathway. The main limitation of this study was the inability to identify the CYP enzymes responsible for the 3-hydroxylation of 4-AP, although this conversion represents only a minor metabolic pathway.ConclusionThere is limited metabolism of 4-AP in humans. The two major metabolites were 3-hydroxy-4-AP and 3-hydroxy-4-AP sulfate, likely through CYP2E1 pathways; the possibility of other CYP enzymes playing a minor role in 4-AP metabolism could not be established unequivocally. Overall, these data suggest that there is a low risk for drug–drug interactions via an impact on 4-AP metabolism through cytochrome pathways.

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“…This approval was based on two Phase 3 clinical trials that demonstrated a significant improvement in walking speed relative to placebo among patients who responded to treatment2,3.…”

Section: Introductionmentioning

confidence: 99%

In vitroevaluation of the effects of 4-aminopyridine on cytochrome P450 enzymes

Caggiano

Blight

2013

Journal of Drug Assessment

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BackgroundDalfampridine extended release tablets (dalfampridine-ER, known as prolonged-, modified, or sustained-release fampridine tablets in some countries) are approved for the improvement of walking in patients with multiple sclerosis (MS). Dalfampridine-ER is an extended release formulation of 4-aminopyridine (4-AP). Dalfampridine-ER is incorporated into MS management strategies that may include disease-modifying and symptomatic therapies. Since several symptomatic therapies are partially or fully metabolized by enzymes of the hepatic cytochrome P450 system (CYP450) it is important to evaluate drug–drug interactions through potential effects of dalfampridine-ER on CYP450.MethodsThe ability of 4-AP to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5 in a direct and time-dependent manner was evaluated using pooled human liver microsomes. 4-AP concentrations were 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM, representing 0.1–100-times the average plasma 4-AP concentration (30 ng/mL; 0.32 μM) at therapeutic dosing; the concentration inhibiting 50% of each enzyme activity (IC50) was determined. The ability of 4-AP (0.025, 0.25, 2.5, and 25 μM) to induce the expression of CYP1A2, 2B6, 2C9, 2C19, 2E1, and 3A4/5 enzymes was evaluated using primary cultures of freshly isolated human hepatocytes from non-transplantable livers. The enzyme-inducing effects of 4-AP were compared with the prototypical inducers. Metabolites were assayed using high-performance liquid chromatography-tandem mass spectrometry techniques. All inhibition and induction assays included positive controls.Results4-AP did not directly inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5, but at a concentration of 30 μM, CYP2E1 was inhibited by 12%, resulting in an estimated IC50 value of 125 μM. None of the enzymes demonstrated time-dependent inhibition by 4-AP. There was little or no effect by 4-AP on enzyme induction, with enzyme activities approximately equivalent to vehicle control. A main limitation was the inability to estimate effectiveness of 4-AP relative to prototypical CYP450 inducers.ConclusionThe likelihood of drug–drug interactions is remote in patients with MS who may be taking dalfampridine-ER concomitantly with medications that are metabolized by CYP450 pathways.

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A phase 3 trial of extended release oral dalfampridine in multiple sclerosis

Abstract: This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.

Cited by 338 publications

References 20 publications

Dalfampridine effects on cognition, fatigue, and dexterity

Dalfampridine effects on cognition, fatigue, and dexterity

Identification of metabolites of dalfampridine (4-aminopyridine) in human subjects and reaction phenotyping of relevant cytochrome P450 pathways

In vitroevaluation of the effects of 4-aminopyridine on cytochrome P450 enzymes

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