cker available as functionally scoredtablets for oral administration.
The chemical name of amifampridine is 3,4-diaminopyridine (CAS 54-96-6).
It is a white to off-white, crystalline solid with a molecular formula of C5H7N3 and a molecularweight of 109.13 g/mol. It is sparingly soluble in water. A 1% aqueous solution of amifampridinehas a pH of 10.8 at 25°C.
The structural formula is:
Each RUZURGI tablet contains 10 mg of amifampridine. Inactive ingredients consist of colloidalsilicon dioxide, dibasic calcium phosphate dihydrate, magnesium stearate, microcrystallinecellulose, and sodium starch glycolate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has notbeen fully elucidated. Amifampridine is a broad spectrum potassium channel blocker.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of RUZURGI on QTc interval prolongation was studied in a double-blind, randomized,placebo- and positive-controlled study in 52 healthy volunteers (including 23 subjects with poormetabolizer phenotype). Study participants were administered 120 mg RUZURGI in 4 equaldoses of 30 mg at 4-hour intervals (Dose 1, 2, 3, and 4)[see Clinical Pharmacology (12.5)].
RUZURGI did not prolong the QTc interval to any clinically relevant extent. In vitro, RUZURGIdid not inhibit the human ether-à-go-go-related gene ion channel.
12.3 Pharmacokinetics
The pharmacokinetics of amifampridine form RUZURGI is approximately dose proportional.
Steady state was generally reached within 1 day of dosing. Multiple dosing resulted in noaccumulation of amifampridine and only moderate accumulation of the 3-N-acetyl amifampridinemetabolite [see Clinical Pharmacology (12.5)].
Absorption
The absolute bioavailabilityof RUZURGI has not been assessed. RUZURGI is absorbed in anapproximately dose-proportional manner with a median time to maximum concentration (tmax) of0.5 hours post administration.
Effect of Food
Compared to administration of RUZURGI in the fasting state, administration of the 20 and 30 mgdose levels of RUZURGI with a standard high fat meal resulted in significant decrease in Cmax(41% and 52%, respectively) and an increase in median tmax to 1.0 hour; AUC0-last was onlysignificantly reduced for the 30 mg dose (23%) [see Dosage and Administration (2.2)].
Distribution
In healthy volunteers, the volume of distribution for plasma amifampridine indicated thatRUZURGI is a drug with a moderate to high volume of distribution.
In vitro human plasma protein binding of amifampridine and 3-N-acetyl amifampridine was
25.3% and 43.3%, respectively.
Elimination
Metabolism
In vitro studies with complimentary DNA expressed human N-acetyltransferase (NAT) enzymepreparations indicate that amifampridine is rapidly metabolized by the N-acetyltransferase 2(NAT2) enzyme to the 3-N-acetyl amifampridine metabolite. Metabolism of amifampridine by Nacetyltransferase1 (NAT1) may also occur but at a much slower rate.
Amifampridine does not undergo glucuronidation or sulfonation.
Excretion
Following oral administration of a single 20 or 30 mg dose of RUZURGI to healthy volunteers,amifampridine apparent oral clearance (CL/F) was 149 to 214 L/h, the average elimination halflife(t1/2) was 3.6 to 4.2 hours. The average t1/2 of the 3-N-acetyl amifampridine metabolite was
4.1 to 4.8 hours.
The majority (>65%) of RU |
