ARGENTUM Exhibit 1102
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
`
`Page 00001
`
`

`
`
`
` _- -nix.-_4_n._ _ -;
`
`—
`
`Contents
`
`Leading Article
`
`[3—Amyloid in Alzheimer’s Disease:
`Therapeutic Implications
`HB Pollard, E Rojas, N Arispe
`
`Practical
`Therapeutics
`
`Management of Benzodiazepine Overdose
`I H5!"-‘-‘F
`
`Acute Bacterial Meningitis: A Practical Guide to
`Treatment
`UB Schaad
`
`1-6
`
`'7-17
`
`18-25
`
`Review Articles
`
`Wi1son’s Disease: Review of Pathophysiology,
`Clinical Features and Drug Treatment
`H Hefter
`
`New Antiepileptic Agents: A Review of Their
`Current Status and Clinical Potential
`PN Patsoio.-LIS Duncan
`
`Sexual Dysfunction Associated with the Drug
`Treatment of Psychiatric Disorders: Incidence
`and Treatment
`DI Stein, E Hollander
`
`Drug Therapy
`
`26-39
`
`Drug Therapy
`
`40-77
`
`Adverse Effects
`
`'78-86
`
`......,
`
`UW PHARMACY L|B3P.t!Y
`
`CNS Drugs is indexed in Current Contentsmflife Sciences, Current Contentswfciinioai Medicine, Science Citation Index”, Scifiairchm,
`Research AIert® and the Medical Documentation Serr.=1'ceT"‘. Indexing by all other major biomedical databases has been applied for.
`Copyright: The appearance of the code at the top of the first page of an article in this journal indicates the copyright owner's
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Page 00003
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`
`New Antiepileptic Drugs
`
`41
`
`treatment strategy. Eterobarb,
`peuticatly since it allows a more rational
`fosphenytoin, oxcarbazepine and rernacernide are prodrugs. This is a particular
`advantage for fosphenytoin, which is metabolised to phenytoin. Gabapentin,
`piracetam and topirainate are not metabolised and vigabatrin is minimally meta-
`bolised. These drugs do not exhibit significant binding to blood proteins. There-
`fore,
`these drugs are not susceptible to significant pharmacokinetic drug
`interactions. Oxcarbazepine also exhibits minimal drug interactions. This is in
`contrast to felbarnate, lamotrigine and stiripentol, drugs with which pharmacokiw
`netic interactions can be clinically problematic.
`All drugs, with the exception of piracetant, are effective treatments for partial
`or secondarily generalised seizures. Piracetam and zonisarnide are effective in
`myoclonus, and felbarnate has been licenced for use in children with Lennox—
`Gastaut syndrome. All 14 drugs have the potential to induce adverse effects,
`mostly CNS—rc-lated. Whilst treatment recommendations can be made for some
`of the drugs, these cannot be considered definitive since they are based largely
`on data from controlled clinicai studies in highly selected patients. Further treat-
`ment recommendations for different seizure types and epilepsy syndromes will
`inevitably develop as clinical experience with the drugs increases.
`
`1. Why are New Antiepileptic
`Drugs Needed?
`
`Epilepsy affects approximately 1% of the world
`population at any one time (about 50 million peo-
`ple worldwide) and is the most common serious
`neurological condition. In the UK, 30 000 to 35
`000 new cases of epilepsy are diagnosed per year.
`resulting in a prevalence of 300 000 patients na-
`tionwide.[1'2] The word ‘epilepsy’ is derived from
`the Greek word ‘E'.1'I:1.7\£1p‘L0'.’ which means ‘to throw
`oneself‘. However. early‘ descriptions of epilepsy
`included ‘the dread disease’, ‘the sacred disease’
`
`and ‘the falling sickness’, and often the victims
`were thought to be ‘bewitched’, ‘inflicted by the
`Gods’ or ‘possessed’.[3'4] ‘Early treatments in-
`cluded powdered human skull, dragon’s blood,
`liver of wolf, stones of swallows and the gall of a
`boar dried with urine.
`
`The first effective antiepileptic drugs were po-
`tassium bromide and phenobarbital (phenobarbi-
`tone).[5-51 The next major advance in the treatment
`of epilepsy was the introduction of phenytoin in
`1938.51 Following the discovery of phenytoin,
`there was an impetus for testing the efficacy of pu-
`tative antiepileptic drugs in animal models of epi-
`
`lepsy. Despite this, only 6 new antiepileptic drugs
`became widely available between 1938 and 1982
`(table 1).
`
`Whilst these standard drugs are invaluable in the
`management of epilepsy. only approximately 70 to
`80% of newly diagnosed patients become seizure-
`free when prescribed these drugs as monotherapy
`regirnens.[3‘10] In these patients, acute and chronic
`CNS adverse effects and idiosyncratic reactions to
`the drugs are not uncommon. The remaining 20 to
`30% of patients whoare refractory to these drugs,
`are usually treated using polytherapy (2 or more
`antiepileptic drugs) regimens. Although this is
`
`'
`
`Table 1. Major antlepilepfic drugs marketed in the UK
`Drug
`Year introduced
`Phenobarbital tphenobarbitonel
`1912
`'
`Phenyloin
`1938
`Primidone
`1952
`Ethosuximida
`1960
`Carbamazepine
`1963
`'
`Clonazeparn
`19?4
`Uhlproic acid (sodium valproate}
`19?4
`Ciobazam
`1982
`Vlgabatrin
`1959
`Larnotrigine
`1991
`Gabapenlin
`1993
`Piraoetern
`1993
`
`9 Adls lnternrnlonol Llrntted. All rights reserved.
`
`CNSDrugs2 m 1994
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`Page 00004
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`

`
`~Putsalos 8 Duncan '
`42
`
`
`helpful to some patients, it can result in problem-
`atic pharmacokinetic and pharmacodynamic drug
`interactions.[11] In the UK, approximately 80 000
`patients have severe treatment—r_efractory epilepsy,
`and these patients obtain little benefit from tradi-
`tional antiepileptic drugs.[2]
`In recent years, the ready availability of thera-
`peutic drug monitoring[12’13] has allowed a better
`understanding of antiepileptic drug pharmacoki—
`netics and howthis relates to adverse effects and
`
`efficacy. In addition, it has been possible to iden-
`tify further problems with these drugs. These in-
`clude common metabolic pathways that can be
`readily inhibited or induced, saturation kinetics,
`the development of tolerance, and narrow thera-
`peutic indexes (i.e. the dose required to produce a
`desirable antiepileptic effect is close to that which
`may cause toxicity).
`The need for new antiepileptic drugs, and pref-
`
`erably for an ‘ideal’ antiepileptic drug, was
`recognised in the late—l970s and ear1y—1980s.
`However, the lack of understanding of the basic
`neuropathology, neuropharmacology and neuro-
`
`physiology of epilepsy greatly hindered the devel-
`opment of such ideal drugs. Instead, research was
`directed towards developing new formulations of
`
`the traditional antiepileptic drugs in an attempt to
`alleviate some of the problematic pharmacokinetic
`properties of these drugs.[”] Advances in this re-
`spect have been the introduction of: (i) 25 and
`50mg capsules of phenytoin, which allow progres-
`sively smaller incremental doses of the drug appro-
`priate to the plasma concentration increases and
`saturation elimination; (ii) enteric-coated valproic
`acid (valproatesodium) tablets to_alleviate drug-
`induced gastrointestinal distress; and (iii) slow re-
`lease (retard) formulations of carbamazepine, de-
`signed to reduce the significant diurnal variation in
`plasma carbamazepine concentrations. This is re-
`quired because high peak plasma concentrations of
`the drug are associated with intermittent toxicity.
`The avoidance of high peak plasma concentrations
`also means that higher dosages can be used, with
`resulting better seizure control.U4l
`
`During the last 20 years, studies of the basic
`mechanisms of epilepsy have revealed both spe-
`cific neuronal relationships and many of the neu-
`rotransmitters and neuromodulators that are con-
`
`sidered important in the control of neuronal
`excitability. Essentially, 2 major hypotheses of
`epileptogenesis of partial seizures and generalised
`convulsions have evolved. First, a hypofunction of
`the major inhibitory neurotransmitter of the brain,
`y—aminobutyric acid (GABA).[15] Secondly," a
`hyperfunction of the amino acids, glutamate and .
`aspartate, which are the major excitatory neuro-
`transmitters in the brain. These latter neuro-
`
`transmitters can activate N-methyl-D-aspartate
`
`(NMDA), on-amino—3-hydroxy—5—methyl-4—isoxa-
`zolepropionic acid (AMPA) and metabotropic re-
`ceptors.[16] Although both hypotheses have been
`substantiated experimentally, the clinical transla-
`tion of these theories has only recently become
`realised.[17] Typical absences, in contrast, are pro-
`voked by GABA acting at GABAA and GABAB
`receptors in the thalamus to activate low threshold
`calcium currents resulting in thalamo cortical os-
`ci1lations.[18]
`.
`
`These hypotheses have opened up anew era of
`molecular design of antiepileptic drugs (the so
`called ‘designer drugs’) and several have recently
`been licenced or are undergoing clinical evalua-
`tion. In addition, various designer drugs are pres-
`ently undergoing preclinical. development, and in-
`clude competitive and noncompetitive NMDA
`receptor antagonists and modulators of the various
`allosteric sites of the NMDA receptor complex.[19]
`The goal of treatment for patients with epilepsy
`is to achieve complete seizure control without ad-
`verse effects. Also, a good quality—of—life outcome
`is highly desirab1e.[20'22] Therefore, an ideal new
`antiepileptic drug should achieve this, and in addi-
`tion be effective against all seizure types and re-
`quire once or twice daily administration. With such
`a profile polytherapy with other antiepileptic drugs
`would be unnecessary and, therefore, metabolism
`and distribution would be minimal considerations.
`
`However, for good measure, and because patients
`with epilepsy would be expected in their lifetime
`
`© Adis International Llmlted. All rights reserved.
`
`CNS Drugs 2(1) 1994
`
`Page 00005
`
`Page 00005
`
`

`
`New Antiepilepl-ic Drugs
`
`43
`
`Table II. Target characteristics of a new antiepiloptic drug
`
`0 As effective as existing antiepileptic drugs
`I Improved therapeutic ratio compared with existing agents
`(is. less toxic in proportion to observed benefit)
`- Ahalf-life of 12 to 24 hours, to allow once- or twice-daily
`administration
`
`I Should not cause drug interactions as a result of inhibition or
`induction of liver enzymes
`o Absence of tolerance or withdrawal problems
`
`to be treated with a variety of drugs for unrelated
`conditions, the ideal drug should not undergo me-
`tabolic degradation and should not bind to blood
`proteins. This would minimise the possibility of
`clinically significant pharmacokinetic drug inter-
`actions. Unfortunately, such an ideal drug is not a
`realistic attainment in the foreseeable future. Thus,
`current drug development is based on the target
`characteristics listed in table II. Also, as the major-
`ity of patients with intractable epilepsy have partial
`seizures, antiepileptic drug_development has been
`targeted towards this seizure type.
`
`2. New Antiepileptic Drugs
`
`In the last decade, there has been an increase in
`
`the availability of putative drugs for clinical eval-
`uation, and clinical trial methodologies have been
`standardised on a worldwide basis. As a result,
`since 1989, 6 new antiepileptic drugs have been
`licenced in Europe (vigabatrin, lamotrigine, garba-
`pentin, oxcarbazepine, felbamate and piracetam),
`2 in the US (felbamate and gabapentin) and 1
`in
`Japan (zonisamide).
`
`In this review, 14 new antiepileptic drugs are
`considered, and these are discussed in alphabetical
`order. For each drug we briefly describe: (a) its
`anticonvulsant profile in animal seizure models
`and, where known, the mechanism of action; (b)
`the clinical pharmacokinetics, including metabo-
`lism and drug interactions; (c) the therapeutic effi-
`cacy (including adverse effects); and (d) indica-
`tions and administration strategy, where known.
`The possible use of rational polytherapy, where
`
`drugs of known but different mechanisms of action
`are combined, is also discussed.
`
`2.1 Eterobcirb
`
`2. I. I Mechanism oi‘ Action
`
`Eterobarb {dirnethoxyniethylphenobarbital; fig.
`1) is a barbiturate that does not enter the brain, but
`is rapidly converted to phenobarbital and a N-
`rnononietlioxymethylplienobarbital metabolite
`(NMMP). As such, eterobarb can be considered a
`phenobarbital prodrug.[23'2“]
`I
`The anticonvulsant profile of eterobarb is some-
`what different to phenobarbital, being more effec-
`tive in the maximal electroshock seizure model
`
`than in the pentetrazol (pentylenetetrazol)-induced
`seizure model.[24~25] Also, eterobarb exhibits an at-
`tenuated sedative and hypnotic activity in rats
`compared with phenobarbital. These differences
`are considered to be the result of the presence of
`NMMP and to reflect a receptor-mediated pharma-
`codynamic interaction between the metabolite and
`phenobarbital. Thus, functional tolerance to the
`hypnotic but not the anticonvulsant effects of the 2
`metabolites occurs.
`
`The exact mechanism of action of eterobarb per
`se is not known. However, it is likely to act, like
`phenobarbital, by postsynaptic modulation of
`GABA and glutamate neurotransmission.
`
`2. L2 Pharmacoklneflcs
`
`absorption of
`administration,
`After oral
`eterobarb is very rapid. Both NMMP and pheno-
`barbital, the 2 primary metabolites of eterobarb,
`are detectable in plasma within 5 minutes. Etern-
`barb is not detectable in blood since it is rapidly
`metabolised in the liver by a first—pass effect.[253
`NMMP concentrations peak in plasma approxi-
`mately 30 minutes after oral ingestion of eterobarb.
`Phenobarbital exhibits a biphasic peak, with an ad-
`ditional peak appearing 3 to 5 hours after eterobarb
`ingestion. This is probably due to the formation of
`phenobarbital from 2 pathways; directly from
`eterobarb (first peak) and from NMMP (second
`peak).m]
`The elimination half-life of NMMP is 4 to 6
`
`hours and that of phenobarbital 4 to 6 days. Be-
`
`© Adis tnternofionol Limited. All rights reserved.
`
`CNS Drugsz (1) 1994
`
`Page 00006
`
`Page 00006
`
`

`
`. Putsulos 8 Duncan
`<
`44
`
`
`N
`>‘°
`N
`
`CH2—O—-CH3
`O
`Eterobarb
`'
`
`H3N+
`
`C02
`
`~
`
`CHQOCONHZ
`/,
`C“
`°”2°°°”"'2
`Felbamaie
`
`/o
`t|=——c
`HN\
`/NcH2oPo3= Nag
`
`Cl
`
`Fosphenytoin
`
`0'
`
`/N\N
`J\
`
`Lamotrigine
`
`(X
`N
`CH3CH2\(I:
`.
`\
`CONH2
`Hz
`Levetiracelam (ucb L059)
`
`0
`
`H 'é'?H
`HC\T/C=Q
`CH—'h)—NH
`0
`Piracetam
`
`I
`
`1
`
`_
`
`’
`
`NH2' HCI
`Rernaoemide
`I
`
`.
`
`U
`
`_
`
`'
`
`4
`
`:,
`
`H
`
`_
`
`.
`
`<0
`
`O
`
`
`
`
`
`. H .
`
`_
`/CH3
`\0;o<H. /C~cH3
`
`r
`
`CH3
`
`J
`
`'
`
`.
`
`_
`
`" H
` H
`
`_HC|
`
`Smpemol
`
`Tlagabine
`
`’
`
`ag/‘K
`
`'
`
`. NH.
`
`,0“
`
`Topiramate
`
`‘
`
`l
`
`'
`
`’ Vigabatrin
`
`Fig. 1.'Str_uctural_forrnu|ae of_a number of new antiepileptic drugs.
`
`cause of limitedyclinical experience with eterobarb,
`significant iphal-macokinetic intefacfions with
`eterobarb per se have not been identified. Hov_v-
`ever,
`interactions commonly encountered with
`phenobarbital; may be anticipated (tables III and
`IV).
`‘
`2
`-
`‘
`'
`-
`‘
`
`2- 7-3 Th!-‘f0P9U"C 5ffiCO_¢Y and AdV9fS9 Fffecfs
`Eterobarb hasbeen undergoing cl1n1ca1evalua—
`t1c_>n as add-on therapy for treatment-refractory pa-
`ti6r1tS for almost 20 years. 0f.130 Patients Studied.
`83 patients have been studied in randomised, open
`label protocols and 47 patients have been studied
`
`to Aclls Infernaflonal Llmtted. All r|gh‘|s reserved.
`
`CNS Drugs 2 (1) 1994
`
`Page 00007
`
`Page 00007
`
`

`
`Table III. Effect of new antiepireptic drugs on plasma
`concentrations of generally available antiepiieptic dmgs
`Drug
`Existing drug
`
`ESMcezadded vPA PB PHT PFIM
`
`
`
`
`
`ETB
`cs-zi
`Esiui
`-
`PHTN —
`vPAl
`FBM
`cezi
`?
`'3
`PHTT
`?
`vPAT
`cez-ET
`cezi
`
`FPHT
`
`Esivll
`
`PBT
`
`-
`
`GPT
`LTG
`LTM
`oxc
`PTM
`RMC
`
`NA
`NA
`CBZ-ET NA
`NA
`'2
`NA
`NA
`NA
`'2
`?
`?
`
`NA
`NA
`NA
`NA
`NA
`?
`
`NA
`NA
`PHTT
`NA
`NA
`?
`
`PRMTl VPAL
`PBT
`NA
`NA
`NA
`NA
`?
`?
`
`NA
`NA
`NA
`NA
`NA
`?
`
`NA
`
`NA
`NA
`NA
`
`STP _
`
`TGB
`TPM
`var
`
`cezt
`CBZ-El
`NA
`NA
`NA
`
`it
`
`NA
`‘.2
`NA
`
`Put
`
`NA
`?
`Pat
`
`PHTT
`
`NA
`NA
`PHTJ.
`
`PFIMT
`PBT
`NA
`7
`Paint
`PBJ.
`NA
`NA
`NA
`NA
`9
`cezt
`zNs
`Abbreviations and sy.-nbeis: GBZ = carbamazepine; CB2-E = cama-
`mazepine epoxide: ESM = ethosuximicle; EFB = eterobarb;
`FEM = ieibarnate: FPHT = tosphenyloin; GPT = gabapentin;
`LTG = lamotrigine: LTM : lavetireoetam (ucb L059); NA = no
`change anticipated: OX0 = oxcarbazepine‘, PB = phenobarbital
`(phenobaibitone); PHT= phonytoin: PRM = primidone: P'|'M = pira-
`cetam; RMC = rernacemide: STF = stiripentol: TGB ='tiagablne:
`TPM = topiram ate: VGT = vigabatrin: \'PA= vaiproic acid (valproate
`sodium); ZNS = zonisamide; - indicates that the combination is
`unlikely to be prescribed; ? indicates an unknown effect; T
`indicates an increase in plasma concentration;
`J.
`indicates a
`decrease in plasma concentration; Tl indicates that an increase
`and a decrease in plasma concentration can occur. depending on
`the relative dose of the interacting drugs.
`
`New Antiepileptic Drugs
`
`using randomised, double-blind, crossover study
`desigr1s.i23'31] All studies involved a comparison
`with phenobarbital. 94 of 130 patients (72%) had _
`fewer seizures (generalised tonic-clonic and partial
`seizures with and without secondary generalisa-
`
`tion) during eterobarb treatment than with pheno-
`barbital treatment, with a mean reduction of 50%
`
`(range 36 to 70%). Furthermore, overall seizure
`intensity was significantly lower during treatment
`with eterobarb than with phenobarbital. Compar-
`
`ing the open label studies with the doubie—blind
`studies, 62 of 83 (75%) and 32 of 47 patients
`(68%), respectively, exhibited significant
`im-
`
`provement in seizure control compared with phe-
`nobarbital.
`High plasma phenobarbital concentrations were
`better tolerated by patients if the phenobarbital was
`derived from eterobarb as opposed to phenobarbi-
`tal per re. A recent randomised, double-blind study
`of 40 male volunteers compared the sedative and
`hypnotic effects of eterobarb and phenobarbital.
`Patients receiving eterobarb tolerated much higher
`plasma phenobarbital _concentrations.[32] The rea-
`son for this better tolerability is not known, but
`may be the result of NMMP binding to phenobar-
`bital receptors.
`A particular problematic adverse effect of phe-
`nobarbital in children is hyperactivity. Of the chil-
`dren studied to date,
`in those presenting with
`hyperactive behaviour during phenobarbital treat-
`ment, symptoms resolved or were markedly atten-
`uated during eterobarb _treatment.[33] These
`changes were also associated with a marked im-
`provement in school performance. Sedation and
`dizziness are the most frequently observed adverse
`effects of eterobarb treatment, in both adults and
`
`children. Three cases of status epilepticus has been
`reported.i3C'l In all 3 cases, status cpilepticus devel-
`oped when patients were taken off eterobarb and
`placed on phenobarbital. As plasma phenobarbital
`concentrations did not change during the switcho-
`ver it is tempting to hypothesise that NMMP has
`additive or synergistic antiepileptic properties.
`
`2. l‘.4 Current‘ treatment Recommendations and
`
`Therapeutic Status
`
`Eterobarb appears to be a superior antiepileptic
`
`drug to phenobarbital and therefore is an attractive
`alternative to the older agent. It is effective in the
`
`management of generalised tonic-clonic and par-
`
`tial seizures, with or without secondary generalisa-
`tion, in both adults and children. Furthermore, it
`
`has significantly fewer adverseeffects than pheno-
`barbital. It_ is not clear to what extent these charac-
`
`teristics are the result of the presence of NMMP.
`The attenuated sedative effect in comparison
`
`with phenobarbital makes eterobarb a particularly
`
`© Acils International Limited. All lights reserved.
`
`CNS Drugs2{l) 1994
`
`Page 00008
`
`Page 00008
`
`

`
`46
`
`Patsalos 51 Duncan
`
`Table IV. Effect of generally available antiepileptic drugs on plasma concentrations of new antiepileptic drugs
`
`Drug
`_‘Existing Qrug,
`’
`p
`_
`A
`p
`I
`_
`g
`.
`.
`1.
`
`added
`ETB
`FBM
`FPHT
`GPT LTG
`LTM oxc
`PTM RMC
`STP
`TGB
`TPM VGT
`ZNS
`caz
`ETBJ,
`FBMJ.
`PHT Tl NA
`LTGJ.
`7
`10-OH-OXCJ, NA
`FlMC~L
`STPL TGBJ,
`TPMJ. NA
`zNsJ,
`PBT
`DGLT
`NA
`'2
`—
`nMc.L
`
`‘
`
`'2
`NA
`
`'
`
`7
`sTPi
`
`7
`TGB.L
`
`?
`7
`
`NA
`NA
`
`7
`zNs¢
`
`ESM
`PB
`
`7
`FBMi
`
`NA
`PHTT
`PHTTJ. NA
`
`NA
`LTC-ii,
`
`7
`?
`
`7
`oxcl
`
`10-OH-OXCJ,
`oxci
`_
`1o-oH-oxcl
`7
`
`_
`
`NA
`
`7
`
`-?
`
`7
`
`N
`
`,
`.
`.
`STPL Teal 'TPM.L NA
`
`zNsl
`
`STPJ, TGBJ.
`r
`
`7
`
`NA
`
`ZNSJ.
`
`PHT
`
`PRM
`
`FBMl
`
`—
`
`LTGJ,
`
`FBMJ,
`
`DGLT
`RMCJ.
`NA
`ETBi
`DGLT
`*
`PBT
`Rivict
`LTG»L
`PHTTJ. NA
`ETBJ,
`DGLT
`V
`—
`PBT
`7
`TPML NA
`?
`NA
`7
`NA
`NA
`?
`LTGT
`PHTTL NA
`NA-
`ETBT
`VPA
`., PBT
`
`Abbreviations and symbols: CBZ = carbamazepine; DGL = deglycinated metabolite of remacemide; ESM = ethosuximide; ETB = eterobarb;
`FBM = felbamate; FPHT = fosphenytoin; GPT = gabapentin; LTG = |a'motrigine; LTM = levetiracetam; NA = no change anticipated;
`10-OH-OXC = 10,11-dihydroxy-carbazepine; OXC = oxcarbazepine; PB ‘= phenobarbital (phenobarbitone); PHT = phenytoin;
`PRM = primidone; PTM = piracetam; RMC = remacemide; STP = stiripentol; TGB = tiagabine; TPM = topiramate; VGT = vigabatrin;
`VPA = valproic acid (valproate sodium); ZNS = zonisamide; 4 indicates that the combination is unlikely to be prescribed; ? indicates an
`unknown effect; T indicates an increase in plasma concentration; i indicates a decrease in plasma concentration; Tl indicates that an increase
`and a decrease in plasma concentration can occur, depending on the dose.
`
`attractive ‘option for children. Also, it would be
`useful in children whose school performance may
`be impaired by hyperactivity that is associated with
`treatment with phenobarbital’. Based on the clinical
`studies to date, it is possible for phenobarbital to
`be substituted with eterobarb on a basis of l to 3.
`
`Thus, a typical dose for eterobarb might be 420
`mg/day in adults.
`
`2.2 Felbamate
`
`2.2.1 Mechanism of Action
`
`The exact mechanism of action of felbamate (2-
`phenyl-1,3-propanediol dicarbonate; fig. 1) is not
`known, but it appears to increase seizure threshold
`and inhibit seizure spread.[34-35] Felbamate blocks
`sustained repetitive firing of neurons by affecting
`voltage—dependent sodium channe1s.[36-37] It also
`blocks convulsions_ secondary to the _voltage-de-
`pendent potassium channel antagonist 4—an1ino—
`pyridine. ‘Ligand binding studies have failed to
`demonstrate any effect of felbamate on GABA or
`benzodiazepine receptors. Felbamate inhibits
`NMDA— and quisqualate-inducedseizures, sug-
`gesting an effect-on excitatory amino acid neu-
`rotransmission. More recently; it has been pro-
`posed that the drug acts via a dual mechanism
`
`affecting both excitatory (NMDA) and inhibitory
`(GABA) mechanisms.[33]
`A
`Felbamate exhibits a unique profile of anticom-
`vulsant action in animal models. It is effective in
`
`maximal electroshock and pentetrazol— and pierc-
`toxin—induced models of epilepsy, but confers no
`protection against bicuculline— and strychnine—in—
`duced seizures.[34’35=39] Based on these models,
`which are predictiveof partial seizures, felbamate
`has ‘a broader spectrum of activity than carbamaz-
`epine or phenytoin. Furthermore, felbamate exhib-
`its particularly low toxicity in these models and
`may also be a neuroprotectant.l4°'43]
`
`2.2.2 Pharmacokinetics
`
`Approximately 90% of orally administered
`felbamate is absorbed, with maximum blood con-
`centrations occurring within 1
`to 4 hours.l44]
`Felbamate is approximately 30% bound to plasma
`proteins, and after hepatic hydroxylation and con-
`jugation the major route ‘of elimination is via the
`urine.[35] The 3 major metabolites offelbamate, the
`oxidative derivatives 2-hyd‘roxy—felbamate and p-
`phenyl-hydroxy—felbamate and the hydrolytic me-
`tabolite 2-phenyl- l ,3-propanediol-monocarbon-
`ate, have not been shown to possess any significant
`
`© Adis International Limited. All rights reserved.
`
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`
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`
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`
`

`
`New Antiepileptic Drugs
`
`47
`
`anticonvulsant or neurotoxic activity in ani-
`mals.[45] The mean elimination half-life of felba-
`
`mate is approximately 20 hours, and no change in
`elimination half-life has been observed after re-
`
`peated administration to healthy volunteers.[45] In
`animals, the pharmacokinetics of felbamate appear
`linear up to a dose of 3600 mg/kg. In patients with
`epilepsy already receiving phenytoin or caIbam-
`azepine. the median half-life of felbamate is re-
`duced to approximately 13 hours.[44] This can be
`attributed to the hepatic enzyn1e—inducing char-
`acteristics of phenytoin and carbamazepine (ta-
`ble IV).
`Felbamate exhibits significant pharmacokinetic
`interactions with phenytoin, carbamazepine and
`valproic acid (table III). Plasma phenytoin and
`carbamazepine concentrations have been reported
`to increase and decrease by 20%, respectively, in
`some patients on introduction of polytherapy with
`felbarnate.[47‘59] The reduction in plasma carbam-
`azepine concentrations has been associated with
`concurrent increases in the pharmacologically ac-
`tive metabolite of carbamazepine, carbamazepine
`epoxide.E47'43=51'52] The exact mechanism of these
`interactions is unlmown.
`
`' In patients taking valproic acid, plasma valproic
`acid concentrations have been increased by ap-
`proximately 28 to 54% during comedication with
`felbamate.[53] This is the first known interaction
`
`with valproic acid whereby plasma valproic acid
`concentrations are increased. The mechanism of
`
`this interaction is unknown, but is most likely to be
`inhibitory. If indeed the mechanism of interaction
`is inhibitory, then its clinical interpretation can be
`misleading. This is because, classically, when a
`plasma drug concentration is increased it is com-
`monly associated with neurotoxicity. However, in
`the case of valproic acid, if one accepts the hypoth-
`esis that one of its many metabolites is responsible
`for the antiepileptic effect, then this interaction
`will result in a loss of seizure control not neuro-
`
`toxicity.
`
`2.2..3 Therapeutic Efficacy and Adverse Effects
`Felbamate was assessed in a double‘-blind,
`
`randomised, placebo-controlled study in 56 pa-
`
`tients with refractory partial seizures who were re-
`ceiving stable dosages of carbamazepine or
`phenytoin as monotherapy. This study showed that
`addition of felbamate to therapy was associated
`with a statistically significant 13.2% reduction in
`seizures compared with placebo.[54] In another 3-
`period, crossover, double-blind, placebo-controb
`led trial involving 30 patients with complex partial
`seizures on carbamazepine monotherapy, felba-
`mate failed on initial analysis to show a significant
`reduction in seizure frequency compared with pla-
`cebo. [55] However, plasma carbamazepine concen-
`trations were lower during felbamate therapy (by a
`mean of 24%). When the data were reanalysed to
`take this into account, it was estimated that there
`
`would have been a seizure frequency reduction of
`50% if carbamazepine plasma concentrations had
`been maintained at the baseline values.
`
`Recently, studies of felbamate using unique de-
`signs have been reported. In the first design, felba-
`mate was studied in presurgical patients with par-
`tial seizures.[56] In these patients, felbamate or
`placebo was administered after withdrawal from
`their normally prescribed antiepileptic drugs as
`part of the presurgical evaluation. Two end points
`were used; time to fourth seizure and the number
`
`of patients completing 28 days of therapy. 15 of 28
`felbamate recipients compared with 4 of 33 pa-
`tients receiving placebo completed the 28 days,
`suggesting a significant antiepileptic effect by
`fCiba1'l'laté‘..[56] However, as plasma concentrations
`of concomitant antiepileptic drugs were not re-
`ported, it is difficult to ascertain any contribution
`that drug interactions may have had on seizure
`control.
`
`The other unique design compared felbamate
`with valproic acid.[57-53] The studies were ran-
`dornised, double-blind and parallel in design. After
`a 56-day baseline period, patients were randomised
`to felbamate (3600 mg/day) or valproic acid (15
`mgfkg/day). During the first 28 days of blinded
`treatment, concomitant antiepileptic drugs were
`discontinued while felbamate or valproic acid were
`added. Patients completed the study either by con-
`tinuing through to 1 12 days of evaluation or requir-
`
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`
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`
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`
`48
`
`Patsalos 8* Duncan
`
`ing withdrawal from the studydue to unacceptable
`seizure exacerbation or lack of seizure control. The
`
`primary efficacy variable was the number of pa-
`tients withdrawing from each treatment group.
`Based on the observation that e56 patients on
`valproic acid and 21 on felbamate withdrew from
`the studies, it was concluded that felbamate has
`
`antiepileptic activity and that it is also effective as
`a monotherapy.[57~58]
`‘
`.
`Felbamate has also been evaluated in 73 chil-
`
`dren. with Lennox—Gastaut syndrome.[59] The
`study design was double-blind, placebo-control-
`led, parallel and add—on. Patients were randomised
`to receive either -felbamate or placebo. Patients
`were either taking— phenytoin or Valproic acid and,
`prior to initiation of study, the dose of. these drugs
`was reduced by 20%. Felbamate treatment was as-
`sociated with a significant decrease in total seizure
`frequency (by 19%) compared-with the placebo
`group (by 4%), and in particular the frequency of
`atonic seizures was reduced (by 34% versus 9% in
`placebo-treated patients). The results achieved in
`this highly treatment—resistant seizure .-syndrome
`-are very encouraging and have been substanti-
`ated-in atfollow-on, open label _study« of these pa-
`tients.[.60] '-Thus, 62% of children who were
`‘switched from. placebo to felbamate had >50% re-
`ductions in astatic and total seizure frequencies at
`1 month, and approximately 50% showed the same
`effect atvl2 months. This has been taken as evi-
`
`dence that tolerance to the antiepileptic effect of
`felbamate does not develop. [60]
`Analysis of adverse effects associated with
`felbamate has been complicated by the problematic
`interactions with concomitant antiepileptic drugs.
`Indeed, many adverse effects ceased after a re-
`duction in the dosage of concomitant antiepileptic
`drugs
`or
`conversion to
`felbamate mono-
`thempy_[5o,54,59]
`-
`.
`_
`_~,
`The most frequently reported adverse. effects
`-during felbamate therapy have been diplopia, in-
`.somnia,. dizziness, blurred visi.on, headache and
`
`mild or moderate in severity. A change in felbamate
`dose has not commonly been required, as the ef-
`fects have generally spontaneously resolved or re-
`solved on reduction of the dose‘ of concomitant
`
`antiepileptic drugs.[54’55’59] With repeated admin-
`istration, bodyweight loss and insomnia have been
`reported with increasingvfrequency. These effects
`appear to be directly related to felbamate rather
`than to effects .of increased concentrations of con-
`
`comitantly administered antiepileptic drugs..All of
`the above adverse effects have been observed in
`
`children. Additionally in children, felbamate may
`be associated with a higher incidence of respiratory
`tract infection than would normally be expected.
`
`2.2.4 Current Therapeutic Status and
`Treatment Recommendations
`
`Felbamate has recently been licenced in the US
`and, several European countries. It is indicated, as
`monotherapy and adjunctive therapy, for the treat-
`ment of partial seizures withand without general-
`isation in adults, and as adjunctive therapy in the
`treatment of partial and generalised seizures asso-
`ciated with Lennox—Gastaut syndrome in children.
`It is available as 400 and 600mg tablets, and as a
`600 mg/_5ml suspension.
`_
`A
`1
`As felbamate has not been systematically eval-
`uated as initial monotherapy, patients should be
`started at a dosage of 1200 mg/day (divided. into3
`or 4 daily doses). The dosage should be increased
`in 600mg increments every _2 weeks,,up to 2400
`mgldaybased on clinical response. If clinically in.-
`dicated, a maximum dosage of 3600 mg/day is rec-
`ommended. When converting patients to.mono-
`therapy, felbamate 1200 mg/day in 3 or‘4 divided
`doses is initiatedeand the dosage of concomitant
`antiepileptic drugs is reduced by, one-third. At
`weeks 2 and 3, felbamate dosage is increased to
`2400 and 3600 mg/day, respectively, while the dos-
`age pf éoncomitant antiepileptic drugs is reduced
`by one—third on each occasion as clinically indi-
`cated.
`Since felbamate is also recommended as an ad-
`
`ataxia. Gastrointestinal distress, including an-
`orexia, nausea and vomiting, have also been re-
`ported. These adverse effects‘ have been typically
`
`junct to other antiepileptic drugs, the increased in-
`cidence .of adverse effects during this type of treat-
`ment regimen may prove «problematic during
`
`'@ Adis International Limited. All rights reserved.
`
`CNS Drugs 2 (1) 1994
`
`Page 00011
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`
`New Antiepileptic Drugs
`
`49
`
`- widespread clinical use. This aspect is particularly
`relevant in Europe where new antiepileptic drugs
`are commonly licenced only as add—on therapy.
`The magnitude of drug interactions between felba-
`mate and other antiepileptic agents