Source: FDA, National Drug Code (US) Revision Year: 2020
The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has not been fully elucidated. Amifampridine is a broad spectrum potassium channel blocker.
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 poor metabolizer phenotype). Study participants were administered 120 mg RUZURGI in 4 equal doses 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, RUZURGI did not inhibit the human ether-à-go-go-related gene ion channel.
The pharmacokinetics of amifampridine form RUZURGI is approximately dose proportional. Steady state was generally reached within 1 day of dosing. Multiple dosing resulted in no accumulation of amifampridine and only moderate accumulation of the 3-N-acetyl amifampridine metabolite [see Clinical Pharmacology (12.5)].
The absolute bioavailability of RUZURGI has not been assessed. RUZURGI is absorbed in an approximately dose-proportional manner with a median time to maximum concentration (tmax) of 0.5 hours post administration.
Compared to administration of RUZURGI in the fasting state, administration of the 20 and 30 mg dose 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 only significantly reduced for the 30 mg dose (23%) [see Dosage and Adminstration (2.2)].
In healthy volunteers, the volume of distribution for plasma amifampridine indicated that RUZURGI 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.
In vitro studies with complimentary DNA expressed human N-acetyltransferase (NAT) enzyme preparations indicate that amifampridine is rapidly metabolized by the N-acetyltransferase 2 (NAT2) enzyme to the 3-N-acetyl amifampridine metabolite. Metabolism of amifampridine by N-acetyltransferase 1 (NAT1) may also occur but at a much slower rate.
Amifampridine does not undergo glucuronidation or sulfonation.
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 half-life (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 RUZURGI administered to healthy volunteers was recovered in urine as either the parent compound or the 3-N-acetyl amifampridine metabolite.
A population pharmacokinetic analysis showed that body weight significantly correlates with the clearance of amifampridine; clearance increased with an increase in body weight. A weight-based dosing regimen is necessary to achieve amifampridine exposures in pediatric patients 6 to less than 17 years of age similar to those observed in adults at effective doses of RUZURGI [see Indications and Usage (1) and Clinical Studies (14)].
Amifampridine is not metabolized by cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.
In vitro studies with human liver microsomes indicated that amifampridine and 3-N-acetyl amifampridine were not direct or time-dependent inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.
In vitro studies in cryopreserved human hepatocytes indicated that amifampridine did not induce CYP isoforms CYP1A2, CYP2B6, or CYP3A4.
Based on in vitro studies with Caco-2 cells amifampridine is unlikely to act as a substrate or inhibitor of the P glycoprotein transporter. Amifampridine is not an inhibitor of the BCRP transporter.
In vitro studies with Chinese hamster ovary cells expressing human OATP1B1, OATP1B3, OAT1, and OCT2 and Madin-Darby canine kidney cells expressing human OAT3 indicated that amifampridine is a weak inhibitor of OCT2, but is not an inhibitor of OAT1, OAT3, OATP1B1, or OATP1B3. The studies also indicated that amifampridine is not a substrate for OAT1, OAT3, or OCT2 transporters.
Controlled clinical drug interaction studies have not been performed with RUZURGI.
Co-administration of intravenous amifampridine and intravenous pyridostigmine led to a 21% elevation in maximum pyridostigmine serum concentrations, but did not significantly affect the pharmacokinetics of amifampridine [see Drug Interactions (7.2)].
Genetic variants in the N-acetyltransferase gene 2 (NAT2) affect the rate and extent of RUZURGI metabolism. In normal healthy volunteers, poor metabolizers, also referred to as “slow acetylators” (i.e., carriers of two reduced function alleles) had higher average plasma amifampridine concentrations than intermediate metabolizers, also referred to as “intermediate acetylators” (i.e., carriers of one reduced and one normal function alleles), and normal metabolizers, also referred to as “fast/rapid acetylators” (i.e., carriers of two normal function alleles).
In the TQT study [see Clinical Pharmacology (12.2)], poor metabolizers (N=19) had 1.1 to 3.7 times higher AUC0-4h and 1.3 to 3.7 times higher Cmax than intermediate metabolizers (N=21), following the first dose. Poor metabolizers had 6.1 to 8.5 times higher AUC0-4h and 3.3 to 7.6 times higher Cmax than normal metabolizers (N=3), following the first dose.
In the general population, the NAT2 poor metabolizer phenotype prevalence is 40–60% in the White and African American populations, and in 10–30% in Asian ethnic populations (individuals of Japanese, Chinese, or Korean descent).
Carcinogenicity studies of amifampridine have not been conducted.
Amifampridine was negative for mutagenicity in an in vitro bacterial reverse mutation (Ames) assay and for clastogenicity in in vivo mouse micronucleus and chromosomal aberration assay. Amifampridine was positive for clastogenicity in an in vitro mouse lymphoma assay in the absence of metabolic activation.
Animal Studies to assess the potential adverse effects of amifampridine on fertility have not been conducted.
The efficacy of RUZURGI for the treatment of LEMS was established by Study 1, a randomized, double-blind, placebo-controlled, withdrawal study (NCT: 01511978). Study 1 enrolled patients with an established diagnosis of LEMS, confirmed by documentation and an independent neurologist review. Patients were required to be on an adequate and stable dosage (30 mg to 100 mg daily for at least 3 months) of RUZURGI prior to entering the study.
The primary measure of efficacy was the categorization of the degree of change (e.g., greater than 30% deterioration) in the Triple Timed Up and Go test (3TUG) upon withdrawal of active medication, when compared with the time-matched average of the 3TUG assessments at baseline.
The 3TUG is a measure of the time it takes a person to rise from a chair, walk 3 meters, and return to the chair for 3 consecutive laps without pause. Higher 3TUG scores represent greater impairment.
The secondary efficacy endpoint was the self-assessment scale for LEMS-related weakness (W-SAS), a scale from -3 to 3 assessing a person’s feeling of weakening or strengthening from baseline. A higher positive W-SAS score indicates a perceived greater improvement of strength. A more negative score indicates perceived greater weakening.
After an initial open-label run-in phase, 32 patients were randomized in a double-blind fashion to either continue treatment with RUZURGI (n=14) or switch to placebo over a 3-day downward titration (n=18) period. Following the downward titration period, patients remained on blinded RUZURGI or placebo for 16 more hours. Efficacy was assessed 2 hours after the last dose of the downward titration period. Patients were allowed to use stable dosages of peripherally-acting cholinesterase inhibitors or oral immunosuppressants. Seventy-nine percent of patients randomized to RUZURGI were receiving cholinesterase inhibitors, versus 83% in the placebo group, and 29% of patients randomized to RUZURGI were receiving an immunosuppressant therapy, versus 39% in the placebo group.
Randomized patients had a median age of 56 years (range: 23 to 83 years), 66% were female, and 91% were White. Ninety-seven percent of patients had a diagnosis of autoimmune LEMS, and 3% of patients had a diagnosis of paraneoplastic LEMS.
All 32 patients completed the study. None of the patients randomized to continue RUZURGI experienced a greater than 30% deterioration in the final post-dose 3TUG test. In contrast, 72% (13/18) of those randomized to placebo experienced a greater than 30% deterioration in the final 3TUG test (p <0.0001). Patients who were randomized to placebo returned to baseline after restarting RUZURGI. Figure 1 shows the time course of the mean percent change from baseline on the 3TUG during the double-blind phase and with reinitiation of RUZURGI.
Figure 1: Mean Percent Change From Baseline in Post-dose 3TUG Time During the Double-blind Phase of the Study and Return to Baseline Upon Reinitiation of RUZURGI
3TUG=Triple Timed Up and Go; A=afternoon; E=evening; M=morning.
The W-SAS score showed a significantly greater decrease in patients randomized to placebo (-2.4) than in those who continued treatment with RUZURGI (-0.2; p <0.0001), indicating that patients who were randomized to placebo perceived a worsening of weakness compared to those who remained on RUZURGI.
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