Absorption, Distribution and Excretion
Orally-administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Tmax, immediate release form = 1 hour; Tmax, extended release form = 3.5 hours; Cmax, 10 mg extended release = 17.3 - 21.6 ng/mL; Relative bioavailability of 10 mg extended-release tablets compared to aqueous oral solution = 96%
Almost all of the dose and its metabolites are completely eliminated by the kidneys after 24 hours. Urine (96%; 90% of total dose as unchanged drug); Feces (0.5%)
10 mg extended release = 2.6 L/kg
Like other aminopyridines, 4-aminopyridine is rapidly absorbed from the gastrointestinal tract into circulation. The compound is readily metabolized in the liver and metabolites are excreted in urine. About 90% of the administered dose, following IV or oral administration, excretes in the urine.
Dalfampridine is rapidly and completely absorbed from the GI tract.
The bioavailability of dalfampridine extended-release tablets is 96% compared with an extemporaneously prepared aqueous oral solution of immediate-release dalfampridine (formerly known as fampridine (4-aminopyridine, 4-AP)). Dalfampridine extended-release tablets result in delayed absorption and a slower increase to lower peak plasma concentrations compared with an aqueous oral solution of the drug, but the extent of absorption (area under the concentration-time curve (AUC)) is not affected. Plasma concentrations and AUC of dalfampridine increase proportionally with dose.
The pharmacokinetics of dalfampridine in adults with multiple sclerosis (MS) are similar to that reported in healthy adults. In adults 29-56 years of age with MS who received a single 10-mg dalfampridine extended-release tablet, the mean peak plasma concentration was 25.23 ng/mL and was attained 3.92 hours after the dose. In healthy fasting adults, a single 10-mg extended-release tablet of the drug resulted in peak concentrations of 17.3-21.6 ng/mL and occurred 3-4 hours after the dose.
For more Absorption, Distribution and Excretion (Complete) data for 4-AMINOPYRIDINE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Not extensively metabolized by the liver therefore drugs effecting the cytochrome P450 enzyme system that are concomitantly administered with dalfampridine are not expected to interact with each other. Metabolites include 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate and both are inactive. CYP2E1 is the enzyme responsible for 3-hydroxylation of dalfampridine.
The specific enzymes involved in the metabolism of fampridine were not identified in laboratory animals, but based on human microsome studies; it was suggested that CYP2E1 could be responsible for hydroxylation in man. In rat, approximately 36% of the parent drug was removed by hepatic first-pass metabolism. Fampridine was metabolized primarily by hydroxylation, followed by sulfate conjugation. Two circulating metabolites were detected in mouse, rat, rabbit, dog and human plasma: 3-hydroxy-4-AP and 3-hydroxy-4-AP sulfate. Although these metabolites were identified in all species, more extensive metabolism was determined in rats and dogs than in humans. In mouse and rat plasma, it was demonstrated that 4-AP-N-oxide was also a circulating metabolite. In human plasma, two unidentified metabolites were present; however, these metabolites accounted for <2% of the radioactivity.
A small portion of dalfampridine dose is metabolized by cytochrome P-450 (CYP) isoenzymes to 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate. These metabolites have no pharmacologic activity on potassium channels. In vitro studies indicate CYP2E1 is the major enzyme responsible for 3-hydroxylation of dalfampridine; other unidentified CYP enzymes play a minor role in 3-hydroxylation of the drug.
Not extensively metabolized by the liver therefore drugs effecting the cytochrome P450 enzyme system that are concomitantly administered with dalfampridine are not expected to interact with each other. 4-Aminopyridine is rapidly absorbed into the bloodstream from the gastrointestinal tract. It is readily broken down, or metabolized, in the liver into removable compounds excreted in urine. After intravenous and oral absoprtion, the metabolites were almost all excreted in the urine. It does not to concentrate or accumulate in skin. 4-Aminopyridine is excreted in urine and rapidly detoxified in the liver (T48, L1090). Metabolites include 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate and both are inactive. CYP2E1 is the enzyme responsible for 3-hydroxylation of dalfampridine.
Route of Elimination: Almost all of the dose and its metabolites are completely eliminated by the kidneys after 24 hours.
Urine (96%; 90% of total dose as unchanged drug);
Feces (0.5%)
Half Life: Immediate release form = 3.5 hours;
Extended release form = 5.47 hours;

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Biological Half-Life
Immediate release form = 3.5 hours; Extended release form = 5.47 hours;
Elimination of fampridine was in a similar range between rats and dogs with a plasma half-life of 1-2 hr, but was slightly prolonged in humans.
The half-life of dalfampridine is 5.2-6.5 hours. The half-life of 3-hydroxy-4-aminopyridine sulfate is 7.6 hours. /in humans/

Toxicity Summary
4-Aminopyridine blocks potassium channels and thereby increases acetylcholine, and possibly noradrenaline, release at nerve terminals (A316). In MS, axons are progressively demyelinated which exposes potassium channels. As a result, there is a leak of potassium ions which results in the repolarization of cells and a decrease in neuronal excitability. The overall impact is the impairment of neuromuscular transmission as it is harder to trigger an action potential.
Dalfampridine inhibits voltage-gated potassium channels in the CNS to maintain the transmembrane potential and prolong action potential. In other words, dalfampridine works to make sure that the current available is high enough to stimulate conduction in demyelinated axons that are exposed in MS patients. Furthermore, it facilitates neuromuscular and synaptic transmission by relieving conduction blocks in demyelinated axons.

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Hepatotoxicity
Dalfampridine has been associated with infrequent serum aminotransferase elevations during therapy and has not been convincingly linked to instances of clinically apparent liver injury. In analyses of safety of dalfampridine in pre-registration controlled trials with 1922 patients with multiple sclerosis, there were no reports of hepatic injury or laboratory evidence of a hepatotoxicity signal. Nevertheless, a few instances of clinically apparent liver injury in patients receiving dalfampridine have appeared in the published literature. In each instance, however, attribution to dalfampridine was not convincing.
Likelihood score: E* (unproven although suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because no information is available on the use of dalfampridine during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
10 mg extended release = 1-3% protein bound

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Toxicity Data
LD50, oral, mouse = 19 mg/kg
LD50, oral, rat = 21 mg/kg
LD50: 20-29 mg/kg (Oral, Rat) (L1090)
LD50: 3.7 mg/kg (Oral, Dog) (L1090)
LD50: 326 mg/kg (Dermal, Rabbit) (L1090)

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Interactions
The depressant effects of morphine (0.1-1 uM) on sensory-evoked dorsal-horn network responses in explants of mouse spinal cord with attached dorsal root ganglia (DRGs) were rapidly restored after addition of 4-aminopyridine (4-AP; 0.1 mM) and major components of these cord responses were stably maintained in the presence of the opiate. Moreover, prior exposure of cord-DRG explants to 0.1 mM 4-AP prevented the depressant effects of 0.1 uM morphine on DRG-evoked dorsal-horn responses, and the effects of 1-10 uM morphine were at least partly antagonized. Increased Ca++ levels (5 uM) attenuated the depression of dorsal horn responses by 1-10 uM morphine and these effects of Ca++ were greatly enhanced in the presence of 4-AP--in some cultures, concentrations of morphine as high as 100 uM were strongly antagonized during test periods up to 2 hours. Receptor assays showed that 0.1 mM 4-AP +/- 5 mM Ca++ had no effect on stereospecific opiate binding, indicating that the antagonist actions of these agents in our cultures do not occur at the level of the opiate receptor. The relevance of our in vitro studies of 4-AP antagonism of opiate-depressant effects on sensory-evoked dorsal-horn network responses for analyses of problems in opiate analgesia has been strengthened by a recent report demonstrating that 4-AP does, in fact, reverse morphine analgesia in rats, as determined by tail flick tests.
The treatment of verapamil toxicity was examined in lightly sedated dogs. Verapamil, administered as a bolus (0.72 mg/kg) followed by a continuous infusion (0.11 mg/kg/min), decreased cardiac output (CO) ... heart rate (HR) ... left ventricular derivative of pressure with respect to time (LV dP/dt) ... mean aortic pressure (AO) ... and stroke volume. ... 4-Aminopyridine (4-AP) increased heart rate, cardiac output, LV dP/dt, and mean aortic pressure. When administered prior to verapamil, 4-AP prevented the development of verapamil toxicity as shown by the significantly higher mean aortic pressure (P less than 0.001), cardiac output (P less than 0.01), and LV dP/dt (P less than 0.01) when 4-AP followed by verapamil was compared to verapamil alone. In conclusion, there does not appear to be a single specific therapy for verapamil toxicity, however it can be partially correctedly presently available pharmacologic therapy and 4-AP.
Because of increased risk of dose-related adverse effects, dalfampridine should not be used in patients receiving other aminopyridines, including extemporaneously prepared formulations; dalfampridine formerly was known as fampridine (4-aminopyridine, 4-AP). Prior to initiation of dalfampridine therapy, any product containing fampridine or 4-aminopyridine should be discontinued, since the active ingredient is the same.

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Non-Human Toxicity Values
LD50 Dog oral 3.7 mg/kg
LD50 Rat oral (males) 14 mg/kg
LD50 Mouse oral 50 mg/kg
LD50 Rat oral (females) 22 mg/kg
For more Non-Human Toxicity Values (Complete) data for 4-AMINOPYRIDINE (12 total), please visit the HSDB record page.

[1]. Sherratt, R.M., H. Bostock, and T.A. Sears, Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres. Nature, 1980. 283(5747): p. 570-2.

[2]. Bouchard, R. and D. Fedida, Closed- and open-state binding of 4-aminopyridine to the cloned human potassium channel Kv1.5. J Pharmacol Exp Ther, 1995. 275(2): p. 864-76.

Therapeutic Uses
Potassium Channel Blockers
Ampyra (dalfampridine) is a potassium channel blocker indicated to improve walking in patients with multiple sclerosis (MS). /Included in US product label/
Distribution of dalfampridine is restricted; the drug is available only through certain specialty pharmacies.

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Drug Warnings
Anaphylactic reactions have been reported rarely in patients receiving dalfampridine. If an anaphylactic or other serious allergic reaction occurs, dalfampridine should be discontinued and should not be restarted.
Dalfampridine can cause seizures. Postmarketing reports indicate that the majority of seizures have occurred in patients receiving the recommended dalfampridine dosage (generally within days to weeks after starting the drug) and in patients without a history of seizures. Some patients had been receiving other drugs that could have increased the risk of seizures or lowered the seizure threshold; in addition, age-related renal dysfunction and resultant increases in plasma dalfampridine concentrations could have contributed to the risk of seizures. Use of a high dalfampridine dosage (e.g., 15 or 20 mg twice daily) increases the risk of seizures. In open-label extension studies in patients with multiple sclerosis (MS), the incidence of seizures was more than 4 times greater at a dosage of 15 mg twice daily compared with that reported with the recommended dosage (10 mg twice daily).
Dalfampridine is contraindicated in patients with a prior history of seizures. The drug has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on EEG; such patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on EEG is unknown and could be substantially higher than that observed in clinical trials.
Urinary tract infections (UTIs) have been reported more frequently in patients receiving dalfampridine (12%) than in patients receiving placebo (8%). If a UTI occurs in a patient receiving dalfampridine, it should be evaluated and treated as clinically indicated.
For more Drug Warnings (Complete) data for 4-AMINOPYRIDINE (12 total), please visit the HSDB record page.

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Pharmacodynamics
Dalfampridine is a board-spectrum lipophillic potassium channel blocker and binds favourably to the open state than closed state of the potassium channel in the CNS. Its pharmacological target are the potassium channels exposed in MS patients. Does not prolong the QTc interval.

C5H6N2

94.11454

94.053

504-24-5

1727

White to off-white solid powder

1.1±0.1 g/cm3

192.7±40.0 °C at 760 mmHg

157 °C

70.3±27.3 °C

0.5±0.4 mmHg at 25°C

1.569

-2.24

1

2

0

7

48

0

NC1=CC=NC=C1

NUKYPUAOHBNCPY-UHFFFAOYSA-N

InChI=1S/C5H6N2/c6-5-1-3-7-4-2-5/h1-4H,(H2,6,7)

pyridin-4-amine

Fampridine; Pyridin-4-amine; 4-aminopyridine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~531.29 mM)
H2O : ~50 mg/mL (~531.29 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (26.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (26.56 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (26.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)