Retigabine
Encyclopedia
Retigabine or ezogabine (USAN
), codenamed D-23129, is an anticonvulsant
used as a treatment for partial epilepsies
. The drug was developed
by Valeant Pharmaceuticals and GlaxoSmithKline
. It was approved by the European Medicines Agency
under the trade name Trobalt on March 28, 2011, and by the United States
Food and Drug Administration
(FDA), under the trade name Potiga, on June 10, 2011.
Retigabine works primarily as a potassium channel opener
—that is, by activating a certain family of voltage-gated potassium channel
s in the brain. This mechanism of action
is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine
and neuropathic pain
.
setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal model
s of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling
of the amygdala
, pentylenetetrazol
, kainate
, NMDA
, and picrotoxin
. Researchers hoped this wide-ranging activity would translate to studies in humans as well.
, randomized, placebo-controlled
Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly
reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment.
A Phase II trial meant to assess the safety and efficacy of retigabine for treating postherpetic neuralgia
was completed in 2009, but failed to meet its primary endpoint
. Preliminary results were reported by Valeant as "inconclusive".
for retigabine on December 30, 2009. The FDA Peripheral and Central Nervous System Drugs Advisory Committee met on August 11, 2010 to discuss the process and unanimously recommended approval of Potiga for the intended indication (add-on treatment of partial seizures in adults). However, the possibility of urinary retention
as an adverse effect was considered a significant concern, and the panel's members recommended that some sort of monitoring strategy be used to identify patients at risk of bladder dysfunction. Potiga was approved by the FDA on June 10, 2010, and is set to become available on the U.S. market after scheduling
by the Drug Enforcement Administration
.
found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. The most common adverse effects were drowsiness
, dizziness
and vertigo
, confusion, and slurred speech
. Less common side effects included tremor
, memory loss, gait
disturbances, and double vision
.
Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment.
s with most commonly used anticonvulsants. It may increase metabolism of lamotrigine
(Lamictal), whereas phenytoin
(Dilantin) and carbamazepine
(CBZ, Tegretol) increase the clearance
of retigabine.
Concomitant use of retigabine and digoxin
may increase serum concentration of the latter. In vitro studies suggest that the main metabolite of retigabine acts as a P-glycoprotein
inhibitor, and may thus increase absorption and reduce elimination of digoxin.
(50–60%), a high volume of distribution
(6.2 L/kg), and a terminal half-life
of 8 to 11 hours. Retigabine requires thrice-daily dosing due to its short half-life.
Retigabine is metabolized
in the liver, by N-glucuronidation
and acetylation
. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.
, a mechanism of action markedly different from than of any current anticonvulsants. This mechanism of action is similar to that of flupirtine
, which is used mainly for its analgesic properties.
"retigabine" was initially published as being under consideration by WHO
in 1996. This was later adopted as the recommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, the USAN Council—a program sponsored by the American Medical Association, the United States Pharmacopeial Convention, and the American Pharmacists Association that chooses nonproprietary names for drug sold in the United States—adopted the same name. In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as the United States Adopted Name
for the drug. The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
), codenamed D-23129, is an anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
used as a treatment for partial epilepsies
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. The drug was developed
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
by Valeant Pharmaceuticals and GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
. It was approved by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
under the trade name Trobalt on March 28, 2011, and by the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA), under the trade name Potiga, on June 10, 2011.
Retigabine works primarily as a potassium channel opener
Potassium channel opener
A potassium channel opener is a type of drug which facilitates ion transmission through potassium channels.Some examples include:* Diazoxide vasodilator used for hypertension, smooth muscle relaxing activity...
—that is, by activating a certain family of voltage-gated potassium channel
Voltage-gated potassium channel
Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state....
s in the brain. This mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
and neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
.
History
Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinicalPre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....
setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling
Kindling model
Kindling is a commonly used model for the development of seizures and epilepsy in which the duration and behavioral involvement of induced seizures increases after seizures are induced repeatedly. The kindling model was first proposed in the late 1960s by Goddard and colleagues...
of the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, pentylenetetrazol
Pentylenetetrazol
Pentylenetetrazol , also known as metrazol, pentetrazol, pentamethylenetetrazol, Cardiazol or PTZ, is a drug used as a circulatory and respiratory stimulant. High doses cause convulsions, as discovered by the Hungarian-American neurologist and psychiatrist Ladislas J. Meduna in 1934...
, kainate
Kainic acid
Kainic acid is a natural marine acid present in some seaweed. It is a specific agonist for the kainate receptor used as an ionotropic glutamate receptor which mimics the effect of glutamate...
, NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
, and picrotoxin
Picrotoxin
Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound, first isolated by Pierre Boullay in 1812. The name "picrotoxin" is a combination of the Greek words "picros" and "toxicon" ....
. Researchers hoped this wide-ranging activity would translate to studies in humans as well.
Clinical trials
In a double-blindDouble-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
, randomized, placebo-controlled
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment.
A Phase II trial meant to assess the safety and efficacy of retigabine for treating postherpetic neuralgia
Postherpetic neuralgia
Postherpetic neuralgia is a neuralgia caused by the varicella zoster virus. Typically, the neuralgia is confined to a dermatomic area of the skin and follows an outbreak of herpes zoster in that same dermatomic area...
was completed in 2009, but failed to meet its primary endpoint
Clinical endpoint
In a clinical research trial, a clinical endpoint generally refers to occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial, but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual...
. Preliminary results were reported by Valeant as "inconclusive".
Regulatory approval
The U.S. Food and Drug Administration accepted Valeant's New Drug ApplicationNew drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
for retigabine on December 30, 2009. The FDA Peripheral and Central Nervous System Drugs Advisory Committee met on August 11, 2010 to discuss the process and unanimously recommended approval of Potiga for the intended indication (add-on treatment of partial seizures in adults). However, the possibility of urinary retention
Urinary retention
Urinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
as an adverse effect was considered a significant concern, and the panel's members recommended that some sort of monitoring strategy be used to identify patients at risk of bladder dysfunction. Potiga was approved by the FDA on June 10, 2010, and is set to become available on the U.S. market after scheduling
Controlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
by the Drug Enforcement Administration
Drug Enforcement Administration
The Drug Enforcement Administration is a federal law enforcement agency under the United States Department of Justice, tasked with combating drug smuggling and use within the United States...
.
Adverse effects
The adverse effectsAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. The most common adverse effects were drowsiness
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
and vertigo
Vertigo
Vertigo is a form of dizziness.Vertigo may also refer to:* Vertigo , a 1958 film by Alfred Hitchcock**Vertigo , its soundtrack** Vertigo effect, or Dolly zoom, a special effect in film, named after the movie...
, confusion, and slurred speech
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
. Less common side effects included tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, memory loss, gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
disturbances, and double vision
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
.
Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment.
Interactions
Retigabine appears to be free of drug interactionDrug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s with most commonly used anticonvulsants. It may increase metabolism of lamotrigine
Lamotrigine
Lamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
(Lamictal), whereas phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
(Dilantin) and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
(CBZ, Tegretol) increase the clearance
Clearance (medicine)
In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics...
of retigabine.
Concomitant use of retigabine and digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
may increase serum concentration of the latter. In vitro studies suggest that the main metabolite of retigabine acts as a P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
inhibitor, and may thus increase absorption and reduce elimination of digoxin.
Pharmacokinetics
Retigabine is quickly absorbed, and reaches maximum plasma concentrations between half an hour and 2 hours after a single oral dose. It has a moderately high oral bioavailabilityBioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
(50–60%), a high volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
(6.2 L/kg), and a terminal half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of 8 to 11 hours. Retigabine requires thrice-daily dosing due to its short half-life.
Retigabine is metabolized
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
in the liver, by N-glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
and acetylation
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.
Mechanism of action
Retigabine acts as a neuronal KCNQ/Kv7 potassium channel openerPotassium channel opener
A potassium channel opener is a type of drug which facilitates ion transmission through potassium channels.Some examples include:* Diazoxide vasodilator used for hypertension, smooth muscle relaxing activity...
, a mechanism of action markedly different from than of any current anticonvulsants. This mechanism of action is similar to that of flupirtine
Flupirtine
Flupirtine is an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names Katadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. Flupirtine is available as "Pruf",Snepdol in India...
, which is used mainly for its analgesic properties.
Name
The International Nonproprietary NameInternational Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
"retigabine" was initially published as being under consideration by WHO
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
in 1996. This was later adopted as the recommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, the USAN Council—a program sponsored by the American Medical Association, the United States Pharmacopeial Convention, and the American Pharmacists Association that chooses nonproprietary names for drug sold in the United States—adopted the same name. In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as the United States Adopted Name
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
for the drug. The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere.