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| Clinical data | |
|---|---|
| Trade names | Trobalt, Potiga |
| Other names | D-23129, ezogabine (USANUS) |
| AHFS/Drugs.com | Professional Drug Facts |
| MedlinePlus | a612028 |
| License data | |
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 60% |
| Protein binding | 60–80% |
| Metabolism | Liverglucuronidation andacetylation.CYP not involved |
| Eliminationhalf-life | 8 hours (mean), range: 7–11 hours[1] |
| Excretion | Kidney (84%) |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
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| KEGG | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.158.123 |
| Chemical and physical data | |
| Formula | C16H18FN3O2 |
| Molar mass | 303.337 g·mol−1 |
| 3D model (JSmol) | |
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Retigabine (INN) orezogabine (USAN) is ananticonvulsant used as an adjunctive treatment forpartialepilepsies in treatment-experienced adult patients.[2] The drug wasdeveloped byValeant Pharmaceuticals andGlaxoSmithKline. It was approved by theEuropean Medicines Agency under the trade nameTrobalt on March 28, 2011, and by theUnited StatesFood and Drug Administration (FDA), under the trade namePotiga, on June 10, 2011. Production was discontinued in June 2017.[3][4]
Retigabine works primarily as apotassium channel opener—that is, by activating a certain family ofvoltage-gated potassium channels in the brain.[5][6][7] Thismechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, includingtinnitus,migraine andneuropathic pain. The manufacturer withdrew retigabine from clinical use in 2017.
Theadverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related.[8] The most common adverse effects weredrowsiness,dizziness,tinnitus andvertigo, confusion, andslurred speech.[9] Less common side effects includedtremor, memory loss,gait disturbances, anddouble vision.[10]In 2013, FDA warned the public that Potiga (ezogabine) can cause blue skin discoloration and eye abnormalities characterized by pigment changes in the retina. FDA does not currently know if these changes are reversible. FDA is working with the manufacturer to gather and evaluate all available information to better understand these events. FDA will update the public when more information is available.[11]Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment.[12][13]
Retigabine appears to be free ofdrug interactions with most commonly used anticonvulsants. It may increase metabolism oflamotrigine (Lamictal), whereasphenytoin (Dilantin) andcarbamazepine (CBZ, Tegretol) increase theclearance of retigabine.[13][14]
Concomitant use of retigabine anddigoxin may increase serum concentration of the latter.In vitro studies suggest that the main metabolite of retigabine acts as aP-glycoprotein inhibitor, and may thus increase absorption and reduce elimination of digoxin.[13]
Retigabine acts as a neuronalKCNQ/Kv7potassium channel opener, a mechanism of action markedly different from that of any current anticonvulsants.[5][6][7] This mechanism of action is similar to that of the chemically similarflupirtine,[15] which is used mainly for its analgesic properties.
The term "channel opener" refers to a shift in the voltage dependence for channel opening towards more negative potentials. This means that KCNQ/Kv7 channels open at more negative potentials in the presence of Retigabine. Recently, it has also been shown that Retigabine stabilizes the open Kv7.2/7.3 channel, making deactivation slower with little change in voltage dependence. This effect of Retigabine is observed at concentrations below 10 micromolar.[16] A similar effect is observed on the homomeric Kv7.2 channel.[17]
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 oralbioavailability (50–60%), a highvolume of distribution (6.2 L/kg), and aterminal half-life of 8 to 11 hours.[14] Retigabine requires thrice-daily dosing due to its short half-life.[8][9][13]
Retigabine ismetabolized in the liver, byN-glucuronidation andacetylation. Thecytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.[13][14]
Among the newer anticonvulsants, retigabine was one of the most widely studied in thepreclinical 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 theanimal models of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electricalkindling of theamygdala,pentylenetetrazol,kainate,NMDA, andpicrotoxin.[18] Researchers hoped this wide-ranging activity would translate to studies in humans as well.[8]
In adouble-blind,randomized, placebo-controlledPhase 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 wassignificantly 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.[8][10][9]
APhase II trial meant to assess the safety and efficacy of retigabine for treatingpostherpetic neuralgia was completed in 2009, but failed to meet its primaryendpoint. Preliminary results were reported by Valeant as "inconclusive".[19]
The U.S. Food and Drug Administration accepted Valeant'sNew Drug Application for retigabine on December 30, 2009.[20] 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).[21][22] However, the possibility ofurinary 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.[21] Potiga was approved by the FDA on June 10, 2010, but did not become available on the U.S. market until it had beenscheduled by theDrug Enforcement Administration.[12]
In December 2011, the U.S.Drug Enforcement Administration (DEA) placed the substance into Schedule V of theControlled Substances Act (CSA), the category for substances with a comparatively low potential for abuse. This became effective 15 December 2011.[23]
TheInternational Nonproprietary Name "retigabine" was initially published as being under consideration byWHO in 1996.[24] This was later adopted as therecommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, theUSAN 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.[25] In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as theUnited States Adopted Name for the drug.[26] The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere.
