DOCSLIB.ORG

Bioavailability File: Rufinamide

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Bioavailability File: Rufinamide FABAD J. Pharm. Sci., 44, 3, 231-242, 2019 REVIEW ARTICLES Bioavailability File: Rufinamide Mehtap SAYDAM* , Sevgi TAKKA**º Bioavailability File: Rufinamide Biyoyararlanım Dosyası: Rufinamit SUMMARY ÖZ Rufinamide is a third-generation, a triazole derivative drug. Rufinamit üçüncü jenerasyon, triazole türevi bir ilaçtır. Lennox- Rufinamide is indicated for treatment of seizures associated with Gastaut sendromunda (LGS) meydana gelen krizlerin tedavisinde Lennox-Gastaut syndrome (LGS). LGS is one of the most severe kullanılır. forms of childhood epilepsy and responsible of approximately 1to LGS, çocukluk tipi epilepsi türevleri arasında en şiddetli gözlenen 4% of all childhood epilepsy cases, especially between 3 and 5 years. türlerden biridir, çocukluk epilepsi vakalarının yaklaşık %1 - 4’ü The etiology of LGS is frequently unknown which makes it difficult arasında, özellikle 3-5 yaşları arasında daha yoğun olarak gözlenir. to control. The condition is characterized by a triad of symptoms, including impairment of cognitive function, slow spike-and-wave Etiyolojisi tam olarak aydınlatılamamış olmakla birlikte, LGS bilişsel complexes on electroencephalogram (EEG) recordings, and multiple bozukluklar, düşük elektroensefalogram dalgalanması ve çoklu krizler seizure types. ile karakterizedir ve kontrol altına alınması zordur. Rufinamide is a lipophilic compound. Water solubility is very low Rufinamit lipofilik bir bileşiktir. Sudaki çözünürlüğü düşüktür and similar across pH values ranging from 1 to 10. Rufinamide is ve pH 1 ile 10 arasında benzerdir. Oral alımın ardından yüksek highly absorbed after oral administration. Food increases the exposure oranda emilir. Yiyecekler rufinamide maruziyetini artırır. Tekli ve to rufinamide. On single and multiple dosing, rufinamide exhibited çoklu dozlamalarda, yüksek dozlarda düşük çözünürlük nedeniyle nonlinear pharmacokinetics in the dose range from 200 mg to 1200 doygunluğa ulaşması sonucunda, 200 mg ve 1200 mg arasında mg, which may be attributed to saturable absorption or limited non-lineer farmakokinetik gösterir. Plazma proteinlerine bağlanma solubility at higher doses. The drug is bound to plasma proteins in low oranı %26-34 arasıdır ve düşük bağlanır. Metabolize olur ve aktif amount (26 to 34 %). Rufinamide is extensively metabolized but metaboliti yoktur. Ana biyotranformasyon yolu karboksilamid has no active metabolites. The primary biotransformation pathway grubundan karboksilesteraz aracılı hidrolizdir. Renal atılım ana is carboxylesterase mediated hydrolysis of the carboxylamide group. atılım yoludur. Renal excretion is the predominant route of elimination for drug related material. Bu yayında Rufinamit’e ait fizikokimyasal ve farmakokinetik In this paper, the physicochemical and pharmacokinetic properties, özellikler, analitik tayin yöntemleri ve farmakolojik özellikleri analytical determination methods and pharmacological properties of derlenmiştir. rufinamide are reviewed. Key Words: Rufinamide, pharmacokinetics, bioavailability, orphan Anahtar kelimeler: Rufinamit, farmakokinetik, biyoyararlanım, drug, lennox-gastaut syndrome, 3rd generation yetim ilaç, lennox-gastaut sendromu, 3. jenerasyon Received: 25.04.2019 Revised: 02.10.2019 Accepted: 04.10.2019 * ORCİD: 0000-0002-3449-5780, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06330 Etiler, Ankara, TURKEY. ** ORCİD: 0000-0001-6451-0497, Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06330 Etiler, Ankara, TURKEY. º Corresponding Author: Sevgi TAKKA Phone: +90 312 2023045 Fax: +90 312 2127958 E-mail: [email protected] 231 Saydam, Takka INTRODUCTION ethanol <methanol < chloroform < DMSO (48 mg/ ml) (Wandera, 2013) Water solubility is similar across Lennox-Gastaut syndrome (LGS) is rare and one pH values ranging from 1 to 10 (EMA, 2007a)(Peruc- of the most severe forms of childhood epilepsy. LGS ca et al., 2008)(Mazzucchelli et al., 2011). Solubility usually affects children between the ages of typically in 0.1 N HCl is 63 mg/mL and simulated intestinal between 3 and 5 years. LGS has a significant morbid- fluid is 59 mg/mL (Mazzucchelli et al., 2011)(Cheung ity and mortality, including multiple seizure types, et al., 1995) (Cardot et al., 1998). The drug is highly mental retardation or a learning disability, general- resistant towards acidic and thermal degradations in ized discharges with slow spike-and-wave complexes comparison to alkaline and oxidation degradations in the EEG (EMA, 2017). Therefore, childhood treat- (Portmann et al., 2010). Mehta et al. (Mehta et al., ment of LGS is important and treatment success is 2013) reported that solid sample is stable at 100°C for uncommon or limited in this condition (Kim et al., 24 hours. Molecular structure is schematized in Fig- 2018)(EMA, 2007a). ure 1. Physicochemical properties are summarized in Current management of LGS is not satisfactory be- Table 1. cause the seizures associated with LGS are frequently unresponsive to standard anticonvulsants, in par- ticular carbamazepine, phenytoin, and barbiturates. The treatment of patients with LGS often involves poly-therapy due to the lack of full response to any single antiepileptic drug (AED). Even when a drug is initially effective, this may not persist long term. Patients usually benefit only minor improvements in seizure frequency and severity (EMA, 2007a). Rufinamide is a triazole derivative used as an AED, structurally unrelated to currently marketed AEDs, which was designated as Orphan for Lennox-Gastaut syndrome by the Committee on Orphan Medicinal Products (COMP) (EMEA/OD/047/04) on 9th Sep- Figure 1. Rufinamide molecular structure tember 2004(EMA, 2011), adopted by the European Commission on 20th October 2004 (EU/3/04/240) (EMA, 2007b) and approved from FDA on 10th Au- Table 1. Physicochemical properties of rufinamide gust 2004 (EMA, 2007b). The earliest clinical studies has been started by Ciba-Geigy in Europe in 1987. Property Reference Novartis, (merging of Ciba-Geigy and Sandoz), con- CAS No 106308-44-5 (EMA, tinued the development until 2001. Eisai Company, 2007a) acquired the worldwide development rights to ru- Molecular C10H8F2N4O (EMA, finamide from Novartis on 6 February 2004 for the formula 2007a) submitted indication and further development work Molecular 238.2 g/mol (EMA, since this date has been carried out by Eisai (EMA, weight 2007a) 2007a). Chemical name 1-[(2,6-difluoro-phenyl) (Wheless methyl]-1H-1,2,3-triazole-4 & Vazquez, In this paper, the physicochemical and pharmaco- carboxamide [INN] 2010)(Wan- kinetic properties, analytical determination methods dera, 2013) and pharmacological properties of rufinamide are re- Solubility Practically insoluble in (Mazzuc- viewed. water (40 mg/L). Partially chelli et al., soluble in methanol, slight- 2011) PHYSICOCHEMICAL PROPERTIES ly soluble in ethanol. Rufinamide is a lipophilic compound with low Melting tem- 230-240˚C (Mehta et al., perature 2013) LogP value between 0.65-0.88 (EMA, 2007a)(Wan- dera, 2013)(Perucca et al., 2008)(Mazzucchelli et al., 2011)(Cardot et al., 1998) with > 10 pKa value (Dalvi et al., 2018). The compound has no ionizable functionality. The increasing order of solubility was as follows: Water (0.642 mg/ml)< isopropyl alcohol < 232 FABAD J. Pharm. Sci., 44, 3, 231-242, 2019 Polymorphism ingredient with high stability for oral or parenteral ad- ministration, together with inorganic or organic, solid Rufinamide shows polymorphism. “Crystal mod- or liquid, pharmaceutically suitable diluents (Port- ifications A, A’, B and C” of the compound have been mann et al., 2011)(Portmann et al., 2004)(Portmann described in US Patents US8076362 B2(Portmann et et al., 2010). al., 2011),US 6740669 Bl (Portmann et al., 2004) and US 7750028 B2 (Portmann et al., 2010). It has been QUANTIFICATION METHODS found that choice of the solvent for the recrystalliza- There are publications regarding the quantifica- tion or recrystallization process can effect the forma- tion of rufinamide in pharmaceutical dosage forms or tion of different polymorphs (A, A’, B, C). in biological media. Most recent HPLC-UV analytical Accordingly, the crystal modification A or A’ fulfils methods are summarized in Table 2. the preconditions for being a pharmaceutical active Table 2. Quantification methods of Rufinamide Column Detection Injection Column Mobile Phase Flow Rate Tempera- Diluent RT Ref. Wavelength Volume ture 10mM ammonium acetate buffer (pH C18, 5 µm, 4.7 ± 0.1, adjusted Mobile (Dalvi et 250 x 4.60 215 nm 1.0 mL/min 40 ˚C 50µL ~15min with glacial ace- phase al., 2018) mm tic acid) : ACN (84.7:15.3) C18, 5 µm, Buffer: ACN (60:40) Mobile (Mehta et 250 x 4.60 293 nm (6.08 g/L KH PO 1.0 mL/min 25˚C 20 µL ~ 5 min 2 4 phase al., 2013) mm in water) C18, 5 µm, Tetrabutyl ammoni- (Annapur- 250 x 4.60 215 nm um hydrogen sul- 1.0 mL/min 30 ˚C 20 µL ACN ~ 4 min na et al., mm phate: ACN (50:50) 2012) C18, 5 µm, MeOH: MeOH : THF : (USP, 125 x 4.60 220 nm 1.0 mL/min 25˚C 20 µL THF ~ 7 min Water (12:5:83) 2017a) mm (50:50) MeOH : THF : ACN: C18, 5 µm, Buffer (15:5:80) MeOH: (USP, 125 x 4.60 210 nm 1.0 mL/min 25˚C 25 µL ~ 7 min (2.7 g/L KH PO in Water 2017b) mm 2 4 water) (40:50:10) C18, 5 µm, Mobile (Kumar et 250 x 4.60 215 nm Water: ACN (40:60) 0.8 mL/min 25˚C 20 µL ~ 4 min phase al., 2013) mm C18, 5 µm, (Patel et al., 125 x 4.60 210 nm Water: ACN (40:60) 1.0 mL/min 25˚C 20 µL ACN ~ 4 min 2014) mm (100A) ODS C18,5 ACN: Buffer (KH- µm, PO ) (30:70) (pH Mobile (Harisudha 210 nm 2 4 1.0 mL/min 25˚C 20 µL ~ 3 min 250 x 4.60 4.5, ortho phos- phase et al., 2013) mm phoric acid) C18, 3.5 µm, MeOH : Water MeOH: (Hutchin- 150 x 4.60 230 nm (35:65) with 0.5 mL/min 40 ˚C 10µL Water - son et al., mm 1 mL/L TFA (80:20) 2010) KH2PO4: Potassium dihydrogen phosphate; ACN: Acetonitrile; MeOH: Methanol; THF: Tetrahydrofuran; TFA: Triflu- oroacetic acid; RT: Retention time of Rufinamide 233 Saydam, Takka CLINICAL PHARMACOLOGY 2010), and in adults (Arzimanoglou et al., 2016).
Load more

Recommended publications
  • Mechanisms of Action of Antiepileptic Drugs
    Review Mechanisms of action of antiepileptic drugs Epilepsy affects up to 1% of the general population and causes substantial disability. The management of seizures in patients with epilepsy relies heavily on antiepileptic drugs (AEDs). Phenobarbital, phenytoin, carbamazepine and valproic acid have been the primary medications used to treat epilepsy for several decades. Since 1993 several AEDs have been approved by the US FDA for use in epilepsy. The choice of the AED is based primarily on the seizure type, spectrum of clinical activity, side effect profile and patient characteristics such as age, comorbidities and concurrent medical treatments. Those AEDs with broad- spectrum activity are often found to exert an action at more than one molecular target. This article will review the proposed mechanisms of action of marketed AEDs in the US and discuss the future of AEDs in development. 1 KEYWORDS: AEDs anticonvulsant drugs antiepileptic drugs epilepsy Aaron M Cook mechanism of action seizures & Meriem K Bensalem-Owen† The therapeutic armamentarium for the treat- patients with refractory seizures. The aim of this 1UK HealthCare, 800 Rose St. H-109, ment of seizures has broadened significantly article is to discuss the past, present and future of Lexington, KY 40536-0293, USA †Author for correspondence: over the past decade [1]. Many of the newer AED pharmacology and mechanisms of action. College of Medicine, Department of anti epileptic drugs (AEDs) have clinical advan- Neurology, University of Kentucky, 800 Rose Street, Room L-455, tages over older, so-called ‘first-generation’ First-generation AEDs Lexington, KY 40536, USA AEDs in that they are more predictable in their Broadly, the mechanisms of action of AEDs can Tel.: +1 859 323 0229 Fax: +1 859 323 5943 dose–response profile and typically are associ- be categorized by their effects on the neuronal [email protected] ated with less drug–drug interactions.
    [Show full text]
  • Chapter 25 Mechanisms of Action of Antiepileptic Drugs
    Chapter 25 Mechanisms of action of antiepileptic drugs GRAEME J. SILLS Department of Molecular and Clinical Pharmacology, University of Liverpool _________________________________________________________________________ Introduction The serendipitous discovery of the anticonvulsant properties of phenobarbital in 1912 marked the foundation of the modern pharmacotherapy of epilepsy. The subsequent 70 years saw the introduction of phenytoin, ethosuximide, carbamazepine, sodium valproate and a range of benzodiazepines. Collectively, these compounds have come to be regarded as the ‘established’ antiepileptic drugs (AEDs). A concerted period of development of drugs for epilepsy throughout the 1980s and 1990s has resulted (to date) in 16 new agents being licensed as add-on treatment for difficult-to-control adult and/or paediatric epilepsy, with some becoming available as monotherapy for newly diagnosed patients. Together, these have become known as the ‘modern’ AEDs. Throughout this period of unprecedented drug development, there have also been considerable advances in our understanding of how antiepileptic agents exert their effects at the cellular level. AEDs are neither preventive nor curative and are employed solely as a means of controlling symptoms (i.e. suppression of seizures). Recurrent seizure activity is the manifestation of an intermittent and excessive hyperexcitability of the nervous system and, while the pharmacological minutiae of currently marketed AEDs remain to be completely unravelled, these agents essentially redress the balance between neuronal excitation and inhibition. Three major classes of mechanism are recognised: modulation of voltage-gated ion channels; enhancement of gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission; and attenuation of glutamate-mediated excitatory neurotransmission. The principal pharmacological targets of currently available AEDs are highlighted in Table 1 and discussed further below.
    [Show full text]
  • Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva
    REVIEW ARTICLE Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva Philip N. Patsalos, FRCPath, PhD*† and Dave J. Berry, FRCPath, PhD† INTRODUCTION Abstract: Blood (serum/plasma) antiepileptic drug (AED) therapeu- Measuring antiepileptic drugs (AEDs) in serum or tic drug monitoring (TDM) has proven to be an invaluable surrogate plasma as an aid to personalizing drug therapy is now a well- marker for individualizing and optimizing the drug management of established practice in the treatment of epilepsy, and guidelines patients with epilepsy. Since 1989, there has been an exponential are published that indicate the particular features of epilepsy and increase in AEDs with 23 currently licensed for clinical use, and the properties of AEDs that make the practice so beneficial.1 recently, there has been renewed and extensive interest in the use of The goal of AED therapeutic drug monitoring (TDM) is to saliva as an alternative matrix for AED TDM. The advantages of saliva ’ fl optimize a patient s clinical outcome by supporting the man- include the fact that for many AEDs it re ects the free (pharmacolog- agement of their medication regimen with the assistance of ically active) concentration in serum; it is readily sampled, can be measured drug concentrations/levels. The reason why TDM sampled repetitively, and sampling is noninvasive; does not require the has emerged as an important adjunct to treatment with the expertise of a phlebotomist; and is preferred by many patients, AEDs arises from the fact that for an individual patient
    [Show full text]
  • Experience with Rufinamide in a Pediatric Population: a Single
    Original Articles Experience With Rufinamide in a Pediatric Population: A Single Center’s Experience Martina Vendrame, MD, PhD*1, Tobias Loddenkemper, MD*†1, Vasu D. Gooty, MD*†, Masanori Takeoka, MD*†, Alexander Rotenberg, MD, PhD*†, Ann M. Bergin, MD*†, Yaman Z. Eksioglu, MD*†, Annapurna Poduri, MD*†, Frank H. Duffy, MD*†, Mark Libenson, MD*†, Blaise F. Bourgeois, MD*†, and Sanjeev V. Kothare, MD*† Rufinamide is a new antiepileptic drug recently ap- with rapid and almost complete oral absorption, low plasma proved as adjunctive treatment for generalized seizures protein-binding, high renal excretion, and low propensity to in Lennox-Gastaut syndrome. We undertook a retro- drug-drug interactions [1,2]. Although these properties spective analysis of 77 patients with refractory epilepsy make rufinamide a potentially useful drug in the treatment and receiving rufinamide to evaluate the drug’s effi- of intractable epilepsy in children, rufinamide is currently cacy, tolerability, safety, and dosing schedules. It ap- only approved for the adjunctive treatment of generalized peared efficacious in diverse epilepsy syndromes, with seizures in Lennox-Gastaut syndrome. the highest responder rate in focal cryptogenic epilep- In this study, we retrospectively analyzed the use of rufi- sies (81.1% of patients with >50% response rate), and namide in children with diverse epilepsy syndromes in a ter- in diverse seizure types, with the highest responder tiary pediatric epilepsy center. We describe the safety, rate in tonic/atonic and partial seizures (48.6% and tolerability, efficacy, and dosing of rufinamide, to identify 46.7% of patients with >50% response rate, respec- the advantages or difficulties of its use across a diverse tively).
    [Show full text]
  • Recommendation from the New Drugs Committee
    Scottish Medicines Consortium Re-submission rufinamide, 100mg, 200mg and 400mg tablets (Inovelon®) No.(416/07) Eisai Limited 10 October 2008 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a re-submission rufinamide (Inovelon®) is accepted for restricted use within NHS Scotland as adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients four years and older. Adjunctive rufinamide significantly reduced the frequency of total seizures and tonic-atonic seizures and significantly improved seizure severity when compared to placebo in patients with LGS. Rufinamide is restricted to use in patients who have failed treatment with or are intolerant of alternative traditional antiepileptic drugs. Overleaf is the detailed advice on this product. Chairman Scottish Medicines Consortium Published 10 November, 2008 1 Indication Adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome in patients four years and older. Dosing information The daily dose should be divided into two equal doses taken morning and evening. Children ≥ 4 years and <30kg not receiving valproate: Initially 200mg daily. Dose may be increased according to clinical response and tolerability by 200mg/day, every two days, up to a maximum recommended dose of 1000mg/day. Children ≥ 4 years and <30kg also receiving valproate: Initially 200mg daily. After a minimum of 2 days the dose may be increased according to clinical response and tolerability by 200mg/day, to the maximum recommended dose of 400mg/day.
    [Show full text]
  • HLA-A*31:01 and Oxcarbazepine- Induced DRESS in a Patient With
    HLA-A*31:01 and Oxcarbazepine-DCX Hyun Kim, PharmD, a, b, c Laura Chadwick, PharmD, a, b Yasir Alzaidi, c Jonathan Picker, MBChB, PhD, a, d, e InducedAnnapurna Poduri, MD, MPH, DRESS f, g Shannon Manzi, PharmDin a,a b Patient With Seizures and Complete Deletion abstract Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy.‍ Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with aClinical Pharmacogenomics Service, dDivision of – Genetics and Genomics, and Departments of bPharmacy eosinophilia and systemic symptoms, Stevens-Johnson syndrome, or and fNeurology, Boston Children’s Hospital, Boston, toxic epidermal necrolysis.‍ The Food and Drug Administration approved Massachusetts; cSchool of Pharmacy, Massachusetts HLA-B*15:02 College of Pharmacy and Health Sciences University, label for oxcarbazepine currently presents information regarding a Boston, Massachusetts; and Departments of ePediatrics pharmacogenomic association with the HLA antigen allele and gNeurology, Harvard Medical School, Harvard University, Boston, Massachusetts and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele.‍ However, unlike carbamazepine, screening for the Dr Kim interpreted the pharmacogenomics testing data and drafted the case report; Dr Chadwick presence of this allele is not routinely recommended before administration interpreted the pharmacogenomics testing
    [Show full text]
  • Update on Newer Aeds What Is Their Role?
    Update on Newer AEDs What is their role? Master Class Nov 2012 Young Epilepsy K.B. Das Learning objectives To understand the role of newer AEDs in managing epilepsy Discuss some newer drugs Assumptions Newer drugs are more efficacious They have novel modes of action Their side effects are less Drug interactions are less They are more cost effective Drug-resistant Epilepsy (ILAE 2010) ‘Failure of adequate trials of two tolerated, appropriate chosen and used AED schedules (where as monotherapy or in combination) to achieve seizure freedom’ Previously : intractable, refractory, difficult epilepsy Cumulative probability of being seizure-free by time from start of treatment and number of antiepileptic drug regimens Lucky 7 ! Brodie ,Neurology 2012 ,78:1548 Zonisamide 2005 Japan 1989, US 2000 Broad spectrum Indications Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adult patients (>18 yrs) Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy Mechanism The mechanism of action of zonisamide is not fully elucidated It appears to act on voltage-sensitive sodium and calcium channels Zonisamide also has a modulatory effect on GABA-mediated neuronal inhibition Dosing 1-2 - 5-8 mg/kg/day ; build up 2 weekly Adults:100mg/day – 200 mg/day – 300- 500mg/day Can be given OD for focal sz Steady state 13 days Half life 105 hrs Zonegran Effectiveness Placebo Zonisamide Sz reduction 16% 51% Very common (>1 in 10) Side Effects Somnolence , dizziness ,loss of appetite Agitation, irritability, confusion, depression, ataxia,memory impairment, diplopia and decreased blood bicarbonate levels.
    [Show full text]
  • 4 Rufinamide Demonstrated in Clinical Trials and Supports Its Use As an Adjunctive Antiepil Eptic Drug Interactions Therapy
    PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 1 5 Number 4 April 20 09 Ruf inamide: Use in Patients with Refractory Epilepsy or Lennox Gastaut Syndrome Marcia L. Buck, Pharm.D., FCCP enno x-Gastaut syndrome (LGS) is a rare in children and adults. 5 Clinical trials in adults L form of epilepsy consisting of multiple receiving rufinamide have demons trated a slow, seizure types , including tonic -atonic “drop but complete , absorption with a bioavailability attacks,” and cog nitive impairment. Many approaching 85%. Peak plasma concentrations patients with LGS require a multi -drug regimen, occur 3 to 6 hours after an oral dose. Food with antiepileptics such as valproic acid, increases the extent of absorption by lamotrigine, or topiramate, as well as approximately 30 to 4 5% and shortens the time corticosteroids or immune globulin. Additional to maximum concentr ations . Rufinamide is therapies have included a ketogenic diet, vagus distributed evenly between erythrocytes and nerve stimulation, and surgical resection. plasma with minimal protein binding (34%). The Despite an aggressive approach to treatment, apparent volume of distribution in adults many patients continue to have frequent receiving 3,200 mg rufinamide/day was 50 L. seizures. 1,2 Rufinamide is extensively metabolized via carboxyleste rase -mediated hydrolysis to inactive Several new agents have been under compounds . On ly 2% of a dose is excreted from investigation over the past decade which may be the body as unchanged drug. The average useful in patients with LGS .1,2 In 2004, elimination half -life of rufinamide in adults is 6 rufinamide was granted orphan drug status in the to 1 2 hours.
    [Show full text]
  • BANZEL™ (Rufinamide) Tablets
    BANZEL™ (rufinamide) Tablets DESCRIPTION BANZEL (rufinamide) is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs (AEDs). Rufinamide has the chemical name 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide. It has an empirical formula of C10H8F2N4O and a molecular weight of 238.2. The drug substance is a white, crystalline, odorless and slightly bitter tasting neutral powder. Rufinamide is practically insoluble in water, slightly soluble in tetrahydrofuran and in methanol, and very slightly soluble in ethanol and in acetonitrile. F N N N F NH2 O BANZEL is available for oral administration in film-coated tablets, scored on both sides, containing 200 and 400 mg of rufinamide. Inactive ingredients are colloidal silicon dioxide, corn starch crosscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate. The film coating contains hypromellose, iron oxide red, polyethylene glycol, talc, and titanium dioxide. CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown. The results of in vitro studies suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide (≥ 1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited sustained repetitive firing of sodium-dependent action potentials (EC50 of 3.8 μM). Pharmacokinetics Overview BANZEL is well absorbed after oral administration. However, the rate of absorption is relatively slow and the extent of absorption is decreased as dose is increased.
    [Show full text]
  • Inovelon, INN-Rufinamide
    SCIENTIFIC DISCUSSION 1 Introduction The Lennox-Gastaut syndrome (LGS) is a rare and one of the most severe forms of childhood epilepsy syndrome. The syndrome usually affects children between the ages of 1 and 8 years (typically between 3 and 5 years), but occasionally has its onset in children who are more than 8 years old. LGS begins in childhood but continues to manifest into adulthood in a large number of patients and has a significant morbidity and mortality. The hallmarks of the disease include the following triad: The presence of multiple seizure types: the most characteristic are tonic-atonic seizures and atypical absences, but tonic-clonic, myoclonic, and partial seizures are also frequently present. Tonic-atonic seizures often provoke sudden falls (commonly called drop attacks) and result in injuries. The presence of generalized discharges with slow spike-and-wave complexes in the electroencephalogram (EEG). The presence of mental retardation or a learning disability. In general, this is represented by a static encephalopathy, although the mental status may worsen in the course of the disease due to multiple causes, such as very frequent occurrence of seizures, sometimes subclinical, frequent head trauma from the falls associated with seizures (drop attacks), and undesirable cognitive effects of the high doses of antiepileptic drugs (AEDs) used to treat this very refractory type of epilepsy. The aetiology of LGS remains unidentified in about half of the cases (cryptogenic LGS), whereas in others, the syndrome results from obvious brain injury (symptomatic LGS). The most common identifiable factor is a history of infantile spasms, occurring in up to one-third of the cases.
    [Show full text]
  • New Antiepileptic Drugs
    Chapter 29 New antiepileptic drugs J.W. SANDER UCL Institute of Neurology, University College London, National Hospital for Neurology and Neurosurgery, Queen Square, London, and Epilepsy Society, Chalfont St Peter, Buckinghamshire New antiepileptic drugs (AEDs) are necessary for people with chronic epilepsy and for improving upon established AEDs as first-line therapy. Since 2000, ten new AEDs have been released in the UK. In chronological order these are: oxcarbazepine, levetiracetam, pregabalin, zonisamide, stiripentol, rufinamide, lacosamide, eslicarbazepine acetate, retigabine and perampanel. Two of these drugs, stiripentol and rufinamide, are licensed as orphan drugs for specific epileptic syndromes. Another drug, felbamate, is available in some EU countries. Their pharmacokinetic properties are listed in Table 1 and indications and a guide to dosing in adults and adolescents are given in Table 2. Known side effects are given in Table 3. Complete freedom from seizures with the absence of side effects should be the ultimate aim of AED treatment and the new AEDs have not entirely lived up to expectations. Only a small number of people with chronic epilepsy have been rendered seizure free by the addition of new AEDs. Despite claims to the contrary, the safety profile of the new drugs is only slightly more favourable than that of the established drugs. The chronic side effect profile for the new drugs has also not yet been fully established. New AEDs marketed in the UK Eslicarbazepine acetate Eslicarbazepine acetate is licensed as an add-on for focal epilepsy. It has similarities to carbamazepine and oxcarbazepine. As such it interacts with voltage-gated sodium channels and this is likely to be its main mode of action.
    [Show full text]
  • WO 2010/015029 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 11 February 2010 (11.02.2010) WO 2010/015029 Al (51) International Patent Classification: (74) Agent: FISHER ADAMS KELLY; Level 29 Comalco A61K 31/19 (2006.01) A61P 25/28 (2006.01) Place, 12 Creek Street, Brisbane, Queensland 4000 (AU). A61K 31/445 (2006.01) A61K 31/35 (2006.01) (81) Designated States (unless otherwise indicated, for every A61P 25/26 (2006.01) A61P 25/18 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/137 (2006.01) A61K 31/4192 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61P 25/08 (2006.01) A61P 25/24 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/AU2009/001000 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 6 August 2009 (06.08.2009) NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (25) Filing Language: English SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 2008904016 6 August 2008 (06.08.2008) AU GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 2008904021 6 August 2008 (06.08.2008) AU ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (71) Applicant (for all designated States except US): GOS- TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, FORTH CENTRE (HOLDINGS) PTY LTD [AU/AU]; ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Level 1, 66 Duporth Avenue, Maroochydore, queensland MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, 4558 (AU).
    [Show full text]