Volume 7, Issue 10 October 2011
One of the exciting new developments in 2011 is the introduction of new antiepileptic drugs for their use in epilepsy. As drugs are approved for use in the United States, epilepsy.com will cover these new agents in order to best guide you, your physician, and other healthcare professionals on the best way to use these new medications. One of the new medications that has recently been approved and will soon be available for use is Ezogabine (Potiga).
Potiga is a trade name for a new drug known as Ezogabine. This drug is important because it prevents seizures in a new way different from currently existing antiseizure medications. Its mechanism of action appears to be enhancement of potassium currents mediated by a particular family of ion channels known as KCNQ. By activating these specific channels on nerve cells, Ezogabine is thought to stabilize these nerve cells and reduce brain excitability. It may also have an impact on another neurotransmitter, known as GABA, which is known to cause the nerve cells to calm in some manner. There are several other seizure drugs that work via increasing GABA in the cell; however, Potiga will be the first drug to prevent seizures by the potassium channel mechanism.
Pharmacology, Pharmacodynamics, Pharmacokinetics
Potiga has a linear pharmacokinetic profile between the doses of 600 mg. to 1200 mg. in patients with epilepsy. This means that as one takes an increasing amount of the drug the level of the drug in the blood will increase proportionally to the dose. This is not true for all seizure drugs. After taking single or multiple oral doses, Ezogabine is rapidly absorbed with a median time to maximum blood levels between 30 minutes to 2 hours after the dose. It is 45% bound to plasma proteins and clinically important interactions with other drugs through displacement from these proteins have not been expected. Ezogabine is extensively metabolized in the liver. This metabolism has no oxidation involved by the cytochrome P450 isoenzyme system.
Co-administration of Ezogabine or Potiga with medications that are inhibitors or inducers of the cytochrome P450 system do not impact the pharmacokinetics of this medication. This is important because this will dictate whether the drug has interactions. This drug is eliminated via the kidney by actively being secreted into the urine. The half life for Ezogabine is seven to eleven hours and the clearance of Ezogabine following IV dosing is approximately .4 to .6 liters per hour per kilogram.
In studies using human liver cells indicated that Ezogabine or Potiga does not inhibit enzyme activity for a number of different isoenzymes. Therefore, Ezogabine is unlikely to affect the pharmacokinetics of substrates of major cytochrome P450 isoenzymes through inhibition or induction mechanisms. Moreover, Ezogabine is neither a substrate nor an inhibitor of P-glycoprotein and efflux transporter. However, there are a number of interactions with Potiga and other medications.
Interactions with Other Antiepileptic Drugs
Potiga can interact with carbamazepine, phenytoin, and lamotrigine. With regards to this, carbamazepine and phenytoin do decrease the amount of Potiga in the system by 31% to 34%, respectively. Therefore, one needs to consider an increase in the dose of Potiga when adding either carbamazepine or phenytoin to it. With regards to lamotrigine, there is an 18% decrease in lamotrigine concentration, but it is unclear whether there should be any type of adjustment made for this.
Interactions with Other Medications
With regards to other agents, Potiga has been found to have an important interaction with digoxin. Data from one study show that there is an inhibition of the P glycoprotein mediated transport of digoxin in a concentration dependent manner, and it may inhibit renal clearance of digoxin. Therefore, if one gives Ezogabine or Potiga at therapeutic doses it could increase serum digoxin levels and it is important to check the blood levels of digoxin if your patient is taking this.
With regards to oral contraceptives, there were no significant alterations of the pharmacokinetics of either estrogen or progesterone. With regards to alcohol, the coadministration of ethanol over 20 minutes and 200 mg. of Ezogabine results in an increase in Ezogabine concentration and it may actually lead to increased side effects related to the medications.
Ezogabine has been evaluated for efficacy as adjunctive therapy in partial onset seizures in three multi-centered, randomized, double-blind placebo controlled trials in 1239 adult patients. The primary end point consisted of the percent change in seizure frequency from baseline in the double-blind treatment phase.
All patients enrolled in these studies were adults, had partial onset seizures with or without secondary generalization and were not adequately controlled with up to three concurrent antiseizure drugs or vagus nerve stimulation. More than 75% of patients were taking two or more other seizure drugs. Patients experienced a minimum of four partial onset seizures every month with no seizure-free period exceeding three to four weeks, with the mean duration of epilepsy of 22 years.
Across the three studies the median baseline seizure frequency ranged from eight to twelve seizures per month. Patients were randomized to total daily maintenance doses of either 600 mg. per day, 900 mg. per day, or 1200 mg. per day, each administered in three equally divided doses. During the titration phase of all three studies treatment was initiated at 300 mg. per day in a dose of 100 mg. three times daily and increased in increments of 150 mg. per day to a target dose. Potiga was then compared to placebo at these various rates.
Potiga reduced seizure frequency at 600 mg., 900 mg., and 1200 mg. per day. The reduction in seizure frequency was 27% for 600 mg. of Potiga; 25% for 900 mg.; and up to 24% seizure reduction for 1200 mg. per day. These were all found to be statistically significant for all of these doses compared to a placebo.
The most concerning side effects related to Potiga are the following:
- Urinary retention or inability to empty the bladder
- Neuropsychiatric symptoms
- Dizziness and somnolence
- QT interval lengthening
- Suicide behavior and ideation
- Withdrawal seizures
With regards to urinary retention, Potiga did cause urinary retention in clinical trials and was reported within the first six months of treatment, but was also observed at later times. It was seen in approximately 2% of patients treated in the open label and placebo controlled epilepsy databases. Of these 29 patients who reported problems, 14 required catheterization. Following discontinuation of Potiga all four patients who required catheterization were able to void spontaneously; however, one of the four required a continuous intermittent self-catheterization afterwards. A condition known as hydronephrosis occurred in two patients, one of whom had associated renal functional impairment. Therefore, because of the increased risk of urinary retention on Potiga, urologic symptoms need to be carefully monitored, particularly for patients with benign prostatic hypertrophy, patients who are unable to communicate clinical symptoms, or patients who use other medications that can affect voiding, such as anticholinergics. In these patients a comprehensive evaluation of urological symptoms prior to and during treatment with Potiga may be appropriate.
Confusional states, psychotic symptoms and hallucinations were reported more frequently as side effects in patients treated with Potiga than in those on placebo. Discontinuations resulting from these reactions were more common in the drug related group. The psychiatric symptoms in the mass majority of patients resolved within seven days of stopping the drug. Rapid titration at greater than the recommended doses appears to increase the risk of these side effects.
Potiga does seem to increase the chances for dizziness and somnolence. In placebo-controlled trials in patients with epilepsy, dizziness is reported in 23% of patients treated with Potiga, but yet only 9% in people treated with a placebo. Somnolence was reported in 22% with Potiga and 12% with placebo. Most of these side effects were considered mild to moderate in intensity.
With regards to QT interval effect, a study of cardiac conduction showed that Potiga does produce a mean 7.7 millisecond prolongation in healthy volunteers, titrated to 400 mg. three times a day. The QT prolonging effect occurred within three hours, so QT intervals should be monitored with Potiga prescribed with medicines known to increase QT interval and in patients with known prolonged QT intervals, such as congestive heart failure, ventricular hypertrophy, hyperchloremia or hypomagnesemia.
As with all seizure drugs it is important to always be wary of issues of depression and or suicidal thoughts associated with seizure medication. This is also the case for Potiga. Because of this it is important that one always be very cautious when prescribing this drug to see if there is any change in mood or behavior. Any change in these behaviors or vocalizing a sense that something is happening with regards to self harm would lead us to discontinue the medication.
As with all seizure drugs when Potiga is stopped it should be withdrawn gradually in order to minimize the potential of increased seizure frequency. Potiga needs to be reduced over a period of at least three weeks in order to safely eliminate the medication.
Ezogabine is considered pregnancy category C. There are no adequate and well controlled studies in pregnant women. Potiga should be used during pregnancy only if the potential benefit justifies its potential risk to the fetus. In animal studies, doses associated with maternal plasma exposures to Ezogabine and its main metabolite did produce developmental toxicity when administered in pregnant rats and rabbits. The maximum doses evaluated were limited by maternal toxicity. Therefore, it is unclear what the effects on humans are. It is important that if one is pregnant while taking this medication that one should enroll in a pregnancy registry, such as the North American Antiepileptic Drug Pregnancy Registry, in order to help gather information on this topic. With regards to nursing mothers, it is not known whether Ezogabine is excreted in human milk. However, Potiga and Ezogabine are present in the milk of lactating rats. Because of the potential for serious side effects in nursing infants from Potiga, a decision should be made whether to discontinue nursing or discontinue the drug, depending on which is the more important risk.
With regards to pediatric patients or children, the safety and effectiveness of Potiga in patients under 18 years of age have not been established. Further studies are clearly needed in order to understand its impact on children.
As opposed to older adults, there are an insufficient number of older patients enrolled in these trials to determine its safety and efficacy. One needs to adjust the dose of medications in patients if 65 years and older. Elderly men with symptomatic benign prostatic hypertrophy could be at increased risk for urinary retention. Patients with renal impairment and hepatic impairment should have dose adjustments made in order to account for these issues.
The medication is supplied in 50, 200, 300, and 400 mg. size pills. The medication is meant to be taken in three times a day dosing and starting at a low dose. It is essential that one consult with their physician before initiating this medication.
In summary, Potiga is another medication that will be helpful for patients with partial onset seizures where other medications have failed. When this drug should be used as opposed to other medications remains an unknown at the time this column was written. The drug does work by new mechanism of action, which may suggest that for some patients who have tried other medications this drug may potentially prevent partial seizures. However, this drug does carry adverse effects, including urinary retention issue, which needs to be carefully monitored, along with other side effects. It is too early to tell where we will place this drug amongst our various other choices for seizures over the long run.
How Can Epilepsy Therapy Project Help
Epilepsy Therapy Project helps by speeding up the process from lab research to clinical use for promising new treatments. We also are an important repository of educational material regarding various seizure treatments and by use of Epilepsy.com or My Seizure Diary, we hope that we are able to help individuals with epilepsy sort out whether Potiga is the right agent for them or whether it is a drug that needs to be avoided. By further research on these issues we hope to improve the quality of life for all individuals with epilepsy.
MARK YOUR CALENDAR:
2012 Epilepsy Pipeline Update Conference
3rd Biennial Conference Networking Forum and the 1st ETP Family Day!
February 2 – 4, 2012 | Hyatt Regency San Francisco, CA
Join us for our 3rd biennial showcase of emerging and established companies presenting their strategies, candidates and development programs. You'll learn how anti-seizure product development is the optimal pathway for CNS therapeutic development because of well-characterized mechanisms, therapeutic approaches, clear clinical endpoints for regulatory studies.
You will be among small, mid, and major CNS companies who present their strategies, product candidates and development programs to potential venture capital, private equity, pharma and biotech investors and partners. Past conferences have included: Cyberonics, Eisai, Lundbeck, Medtronic, Pfizer, Sunovion, SK Lifesciences, Valeant Pharmaceuticals and UCB, as well as private companies such as Advanced NeuroMetrics, Asklepios Biopharmaceuticals, Catalyst Pharma, Marinus Pharmaceuticals, MedGenesis Therapeutix, Medkura, NeuroGenomX, NeuroPace, NeuroTherapeutics, NeuroVista, Supernus Pharmaceuticals, and Visualase.
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Hallway Conversations, a series of audio podcasts in which Dr. Joseph Sirven, Editor-in-Chief of epilepsy.com, has the pleasure of having a brief conversation with thought leaders and newsmakers in the field of epilepsy on a range of seizure related topics. The series is intended as a second opinion to help clinicians understand the latest research as explained by the investigator or perhaps focus on a clinical issue with the help of a leading epilepsy authority on the topic. The purpose is to frame the latest epilepsy news in the right context so as to better manage patients with seizures and improve quality of life. We hope that you find the series informative and helpful and that you join us in listening on a regular basis.
Listen to the latest podcasts from 2011 in the Hallway Conversations series from:
October 21, 2011
Gregory Krauss, MD
Johns Hopkins Medical School
October 14, 2011
Bassel Abou-Khalil, MD
Robert L. Macdonald, M.D., Ph.D., Professor and Chairman of Neurology
Vanderbilt University Medical Center
September 14, 2011
Daniel J. Curry, MD
Director of Pediatric Surgical Epilepsy and Functional Neurosurgery
Texas Children's Hospital
Assistant Professor of Neurological Surgery
Baylor College of Medicine
Topic: Visualase surgical technique for epilepsy
Interested In Participating?
If you are interested in participating in a Hallway Conversation interview, please contact ETP at: firstname.lastname@example.org