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Mechanism of Action
The mechanism by which ezogabine exerts its therapeutic effects has not been fully elucidated. In vitro studies indicate that ezogabine enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5) family of ion channels. By activating KCNQ channels, ezogabine is thought to stabilize the resting membrane potential and reduce brain excitability. In vitro studies suggest that ezogabine may also exert therapeutic effects through augmentation of GABA-mediated currents.
The QTc prolongation risk of POTIGA was evaluated in healthy subjects. In a randomized, double-blind, active- and placebo-controlled parallel-group study, 120 healthy subjects (40 in each group) were administered POTIGA titrated up to the final dose of 400 mg 3 times daily, placebo, and placebo and moxifloxacin (on day 22). After 22 days of dosing, the maximum mean (upper 1-sided, 95% CI) increase of baseline- and placebo-adjusted QTc interval based on Fridericia correction method (QTcF) was 7.7 msec (11.9 msec) and was observed at 3 hours after dosing in subjects who achieved 1,200 mg per day. No effects on heart rate, PR, or QRS intervals were noted.
Patients who are prescribed POTIGA with medicines known to increase QT interval or who have known prolonged QT interval, congestive heart failure, ventricular hypertrophy, hypokalemia, or hypomagnesemia should be observed closely [see WARNINGS AND PRECAUTIONS].
The pharmacokinetic profile is approximately linear in daily doses between 600 mg and 1,200 mg in patients with epilepsy, with no unexpected accumulation following repeated administration. The pharmacokinetics of ezogabine are similar in healthy volunteers and patients with epilepsy.
After both single and multiple oral doses, ezogabine is rapidly absorbed with median time to maximum plasma concentration (Tmax) values generally between 0.5 and 2 hours. Absolute oral bioavailability of ezogabine relative to an intravenous dose of ezogabine is approximately 60%. High-fat food does not affect the extent to which ezogabine is absorbed based on plasma AUC values, but it increases peak concentration (Cmax) by approximately 38% and delays Tmax by 0.75 hour.
POTIGA can be taken with or without food.
Data from in vitro studies indicate that ezogabine and NAMR are approximately 80% and 45% bound to plasma protein, respectively. Clinically significant interactions with other drugs through displacement from proteins are not anticipated. The steadystate volume of distribution of ezogabine is 2 to 3 L/kg following intravenous dosing, suggesting that ezogabine is well distributed in the body.
Ezogabine is extensively metabolized primarily via glucuronidation and acetylation in humans. A substantial fraction of the ezogabine dose is converted to inactive Nglucuronides, the predominant circulating metabolites in humans. Ezogabine is also metabolized to NAMR that is also subsequently glucuronidated. NAMR has antiepileptic activity, but it is less potent than ezogabine in animal seizure models. Additional minor metabolites of ezogabine are an N-glucoside of ezogabine and a cyclized metabolite believed to be formed from NAMR. In vitro studies using human biomaterials showed that the N-acetylation of ezogabine was primarily carried out by NAT2, while glucuronidation was primarily carried out by UGT1A4, with contributions by UGT1A1, UGT1A3, and UGT1A9.
In vitro studies showed no evidence of oxidative metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of ezogabine with medications that are inhibitors or inducers of cytochrome P450 enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine or NAMR.
Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%.
Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t/2) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is actively secreted into the urine.
Race: No study has been conducted to investigate the impact of race on pharmacokinetics of ezogabine. A population pharmacokinetic analysis comparing Caucasians and non-Caucasians (predominately African American and Hispanic patients) showed no significant pharmacokinetic difference. No adjustment of the ezogabine dose for race is recommended.
Gender: The impact of gender on the pharmacokinetics of ezogabine was examined following a single dose of POTIGA to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. The AUC values were approximately 20% higher in young females compared to young males and approximately 30% higher in elderly females compared to elderly males. The Cmax values were approximately 50% higher in young females compared to young males and approximately 100% higher in elderly females compared to elderly males. There was no gender difference in weight-normalized clearance. Overall, no adjustment of the dosage of POTIGA is recommended based on gender.
Pediatric Patients: The pharmacokinetics of ezogabine in pediatric patients have not been investigated.
Geriatric: The impact of age on the pharmacokinetics of ezogabine was examined following a single dose of ezogabine to healthy young (aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. Systemic exposure (AUC) of ezogabine was approximately 40% to 50% higher and terminal half-life was prolonged by approximately 30% in the elderly compared to the younger subjects. The peak concentration (Cmax) was similar to that observed in younger subjects. A dosage reduction in the elderly is recommended [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Renal Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of POTIGA in subjects with normal (CrCL > 80 ml/min), mild (CrCL ≥ 50 to < 80 mL/min), moderate (CrCL ≥ 30 to < 50 mL/min), or severe renal impairment (CrCL < 30 mL/min) (n = 6 in each cohort) and in subjects with ESRD requiring hemodialysis (n = 6). The ezogabine AUC was increased by approximately 30% in patients with mild renal impairment and doubled in patients with moderate impairment to ESRD (CrCL < 50 mL/min) relative to healthy subjects. Similar increases in NAMR exposure were observed in the various degrees of renal impairment. The effect of hemodialysis on ezogabine clearance has not been established. Dosage reduction is recommended for patients with creatinine clearance < 50 mL/min and for patients with ESRD receiving dialysis [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Hepatic Impairment: The pharmacokinetics of ezogabine were studied following a single 100-mg dose of POTIGA in subjects with normal, mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to 9), or severe hepatic (Child-Pugh score > 9) impairment (n = 6 in each cohort). Relative to healthy subjects, ezogabine AUC was not affected by mild hepatic impairment, but was increased by approximately 50% in subjects with moderate hepatic impairment and doubled in subjects with severe hepatic impairment. There was an increase of approximately 30% in exposure to NAMR in patients with moderate to severe impairment. Dosage reduction is recommended for patients with moderate and severe hepatic impairment [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
In vitro studies using human liver microsomes indicated that ezogabine does not inhibit enzyme activity for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. Inhibition of CYP2B6 by ezogabine has not been evaluated. In addition, in vitro studies in human primary hepatocytes showed that ezogabine and NAMR did not induce CYP1A2 or CYP3A4/5 activity. Therefore, ezogabine is unlikely to affect the pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through inhibition or induction mechanisms.
Ezogabine is neither a substrate nor an inhibitor of P-glycoprotein, an efflux transporter. NAMR is a P-glycoprotein inhibitor. Data from an in vitro study showed that NAMR inhibited P-glycoprotein-mediated transport of digoxin in a concentration-dependent manner, indicating that NAMR may inhibit renal clearance of digoxin. Administration of POTIGA at therapeutic doses may increase digoxin serum concentrations [see DRUG INTERACTIONS].
Interactions with Antiepileptic Drugs: The interactions between POTIGA and concomitant AEDs are summarized in Table 6.
Table 6: Interactions Between POTIGA and Concomitant
|AED||Dose of AED (mg/day)||Dose of POTIGA (mg/day)||Influence of POTIGA on AED||Influence of AED on POTIGA||Dosage Adjustment|
|Carbamazepinea,b||600-2,400||300-1,200||None||31% decrease in AUC, 23% decrease in Cmax, 28% increase in clearance||consider an increase in dosage of POTIGA when adding carbamazepinec|
|Phenytoina,b||120-600||300-1,200||None||34% decrease in AUC, 18% decrease in Cmax, 33% increase in clearance||consider an increase in dosage of POTIGA when adding phenytoinc|
|Lamotrigine||200||600||18% decrease in AUC, 22% increase in clearance||None||None|
|a Based on results of a Phase 2 study.
b Inducer for uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs).
c A decrease in dose of POTIGA should be considered when carbamazepine or phenytoin is discontinued.
d Zonisamide, valproic acid, clonazepam, gabapentin, levetiracetam, oxcarbazepine, phenobarbital, pregabalin, topiramate, clobazam, and lamotrigine, based on a population pharmacokinetic analysis using pooled data from Phase 3 clinical trials.
Oral Contraceptives: In one study examining the potential interaction between ezogabine (150 mg 3 times daily for 3 days) and the combination oral contraceptive norgestrel/ethinyl estradiol (0.3 mg/0.03 mg) tablets in 20 healthy females, no significant alteration in the pharmacokinetics of either drug was observed.
In a second study examining the potential interaction of repeated ezogabine dosing (250 mg 3 times daily for 14 days) and the combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg) tablets in 25 healthy females, no significant alteration in the pharmacokinetics of either drug was observed.
Alcohol: In a healthy volunteer study, the coadministration of ethanol 1g/kg (5 standard alcohol drinks) over 20 minutes and ezogabine (200 mg) resulted in an increase in the ezogabine Cmax and AUC by 23% and 37%, respectively [see DRUG INTERACTIONS].
The efficacy of POTIGA as adjunctive therapy in partial-onset seizures was established in 3 multicenter, randomized, double-blind, placebo-controlled studies in 1,239 adult patients. The primary endpoint consisted of the percent change in seizure frequency from baseline in the double-blind treatment phase.
Patients enrolled in the studies had partial onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs, with or without concomitant vagus nerve stimulation. More than 75% of patients were taking 2 or more concomitant AEDs. During an 8-week baseline period, patients experienced at least 4 partial onset seizures per 28 days on average with no seizure-free period exceeding 3 to 4 weeks. Patients had a mean duration of epilepsy of 22 years. Across the 3 studies, the median baseline seizure frequency ranged from 8 to 12 seizures per month. The criteria for statistical significance was P < 0.05.
Patients were randomized to the total daily maintenance dosages of 600 mg per day, 900 mg per day, or 1,200 mg per day, each administered in 3 equally divided doses. During the titration phase of all 3 studies, treatment was initiated at 300 mg per day (100 mg 3 times per day) and increased in weekly increments of 150 mg per day to the target maintenance dosage.
Figure 1 shows the median percent reduction in 28-day seizure frequency (baseline to double-blind phase) as compared with placebo across all 3 studies. A statistically significant effect was observed with POTIGA at doses of 600 mg per day (Study 1), at 900 mg per day (Studies 1 and 3), and at 1,200 mg per day (Studies 2 and 3).
Figure 1: Median Percent Reduction From Baseline in
Seizure Frequency per 28 Days by Dose
Figure 2 shows changes from baseline in the 28-day total partial seizure frequency by category for patients treated with POTIGA and placebo in an integrated analysis across the 3 clinical trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in five categories.
Figure 2: Proportion of Patients by Category of
Seizure Response for POTIGA and Placebo Across All Three Double-blind Trials
Last reviewed on RxList: 9/19/2013
This monograph has been modified to include the generic and brand name in many instances.
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