Epilepsy & Behavior 20 (2011) 20–23
`
`Contents lists available at ScienceDirect
`
`Epilepsy & Behavior
`
`j ou r n a l h o m e pa g e : ww w. e l s ev i e r. c o m/ l o c a t e / ye b e h
`
`Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking
`antiepileptic drugs: A pharmacodynamic interaction?
`Jan Novy a, Philip N. Patsalos a, Josemir W. Sander a,b, Sanjay M. Sisodiya a,⁎
`a Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
`b SEIN—Epilepsy Institute in The Netherlands Foundation, Achterweg 5, 2103SW Heemstede, The Netherlands
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 31 August 2010
`Revised 29 September 2010
`Accepted 3 October 2010
`Available online 5 November 2010
`
`Keywords:
`Lacosamide
`Interaction
`Pharmacodynamics
`Sodium voltage-gated channel
`Drug load
`
`1. Introduction
`
`Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data
`from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-
`gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of
`tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia,
`dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we
`identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were
`ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to
`have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-
`inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-
`blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during
`lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment.
`© 2010 Elsevier Inc. All rights reserved.
`
`Lacosamide was recently licensed as an add-on antiepileptic drug
`(AED) for partial epilepsy. Clinical trial data suggest it has a response
`rate (N50% reduction in seizure frequency) of 35–41% at doses
`between 400 and 600 mg daily [1–3]. Oral lacosamide is almost
`completely absorbed and reaches its maximal concentration within 1
`to 4 hours, with a half-life of 13 hours [4]. It has a favorable pharma-
`cokinetic profile, as it is mostly excreted unchanged in urine. It has
`minor hepatic metabolism (cytochrome P450 2C19), but displays
`no significant pharmacokinetic interaction [5,6]. Lacosamide was
`shown to act by enhancing slow inactivation of voltage-gated sodium
`channels (VGSCs), believed to be a new mechanism of action, as
`other VGSC-blocking AEDs (carbamazepine, phenytoin, lamotrigine,
`oxcarbazepine) act on fast inactivation [7]. Lacosamide also binds to
`CRMP-2, an intracellular signal protein involved in neuronal differ-
`entiation and growth [8]. This putative mechanism, which was also
`recently suggested to modulate its action on VGSCs [9], is still debated.
`Lacosamide is generally well tolerated, with mostly dose-dependent
`central nervous system side effects (dizziness, diplopia, blurred vision,
`somnolence, or headache) [3]. In a postmarketing series of 25 people
`treated with lacosamide, 3 concomitantly taking other VGSC-blocking
`
`AEDs discontinued treatment because of side effects, but it was assumed
`that this was not due to an interaction between the AEDs [10].
`We report a series of seven people with epilepsy who experienced
`significant neurotoxicity during the introduction of lacosamide in
`association with other VGSC-blocking AEDs, and our data suggest this
`is likely to be due to a pharmacodynamic interaction.
`
`2. Case reports
`
`We reviewed the notes of all the people seen by two clinicians at
`specialized epilepsy clinics of the National Hospital for Neurology and
`Neurosurgery who reported neurotoxicity events (45 individuals).
`None of 6 people on lacosamide in combination with other non-VGSC-
`blocking AEDs experienced such an interaction. Among 39 people
`experiencing neurotoxicity on a combination of lacosamide and other
`VGSC-blocking AEDs, 9 experienced an interaction between lacosamide
`and VGSC-blocking AEDs; 2 of these were excluded as there were
`insufficient drug level data.
`The demographics, diagnoses, and previous AED medications for
`the seven people reported are summarized in Table 1. AED serum
`levels are detailed in Table 2.
`
`2.1. Case 1
`
`⁎ Corresponding author. Department of Clinical and Experimental Epilepsy, UCL
`Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
`E-mail address: s.sisodiya@ion.ucl.ac.uk (S.M. Sisodiya).
`
`1525-5050/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
`doi:10.1016/j.yebeh.2010.10.002
`
`On levetiracetam (2500 mg daily), oxcarbazepine (1800 mg), and
`clobazam (10 mg), this woman continued to experience monthly
`seizures. She started lacosamide and the dose was increased over
`2 months to 200 mg/day. There was a significant decrease in seizure
`ARGENTUM Exhibit 1148
` Argentum Pharmaceuticals LLC v. Research Corporation Technologies, Inc.
`IPR2016-00204
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`Page 00001
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`21
`
`Table 1
`Demographics, diagnosis and previous antiepileptic medication of the patients.
`
`Case
`
`1. Female, age 26
`
`2. Male, age 22
`
`3. Female, age 37
`
`Diagnosis
`
`Previously tried antiepileptic drugs
`
`Symptomatic epilepsy with complex partial and generalized seizures
`Left periventricular heterotopia
`
`Lamotrigine
`
`Cryptogenic right frontal epilepsy with
`complex partial and generalized tonic–clonic seizures
`
`Valproate, levetiracetam
`topiramate, zonisamide, topiramate
`
`Cryptogenic frontal lobe epilepsy with complex partial seizures,
`generalized tonic–clonic seizures, and drop attacks
`
`Carbamazepine, valproate, acetazolamide
`gabapentin, topiramate, felbamate, levetiracetam
`oxcarbazepine, zonisamide, tiagabine, phenobarbital
`
`4. Female, age 77
`
`Cryptogenic partial epilepsy with complex partial seizures
`
`Lamotrigine, carbamazepine, levetiracetam
`
`5. Female, age 24
`
`6. Female, age 36
`
`Multifocal epilepsy with simple and complex partial seizures
`Learning disability and dysmorphism (4p trisomy)
`
`Valproate, topiramate, clobazam
`valproate, topiramate, gabapentin, clobazam
`
`Symptomatic epilepsy with partial seizures
`Resection and radiotherapy of low-grade astrocytoma
`Communicating hydrocephalus with ventriculoperitoneal shunt
`
`Carbamazepine, valproate, vigabatrin
`lamotrigine, gabapentin, phenobarbital
`
`7. Female, age 47
`
`Symptomatic epilepsy with simple partial and generalized seizures
`Right temporoparietal dysplasia
`
`Phenobarbital, phenytoin, topiramate, vigabatrin,
`carbamazepine, valproate, clobazam, acetazolamide,
`lamotrigine, methsuximide, felbamate, gabapentin, tiagabine
`
`frequency, but when the dose of 200 mg/day was reached, she
`experienced recurrent episodes of diplopia and ataxia. Serum levels of
`concomitant AEDs did not show any significant change after the
`introduction of lacosamide. Serum levels of lacosamide were below
`the reference range [11]. As seizure frequency had decreased
`significantly, oxcarbazepine was reduced to 1500 mg with improve-
`ment of the symptoms, allowing the gradual increase in lacosamide up
`to 300 mg/day over 4 weeks. Symptoms recurred when she reached
`300 mg/day, alleviated by a further decrease in oxcarbazepine to
`
`1350 mg. She continued to have significant seizure reduction and was
`able to increase lacosamide to 350 mg/day without additional adverse
`events.
`
`2.2. Case 2
`
`On carbamazepine retard 1800 mg per day, this man continued to
`have two seizures weekly. Lacosamide was started with a view
`toward increasing the dose to 200 mg/day over 6 weeks. It was well
`
`Table 2
`Serum levels of the antiepileptic drugs.
`
`Case
`
`Antiepileptic drug/metabolite
`
`Serum level (μmol/L)
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`10-Hydroxycarbazepine
`Levetiracetam
`Lacosamide
`
`Carbamazepine
`Carbamazepine epoxide
`Lacosamide
`
`Phenytoin
`Lamotrigine
`Lacosamide
`
`10-Hydroxycarbazepine
`Lacosamide
`
`Carbamazepine
`Carbamazepine epoxide
`Levetiracetam
`Lacosamide
`
`10-Hydroxycarbazepine
`Topiramate
`Phenytoin
`Lacosamide
`
`10-Hydroxycarbazepine
`Levetiracetam
`Lacosamide
`
`Before lacosamide introduction
`
`At the time of the symptoms
`
`After VGSC-blocking AED reduction
`
`103
`161
`—
`
`47.7
`4.2
`—
`
`108
`197
`21
`
`49.8
`4.8
`5
`
`—
`—
`—
`
`—
`—
`—
`
`80 (1 h after dosing)
`8 (1 h after dosing)
`-
`
`99 (3 h after dosing)
`13 (3 h after dosing)
`29 (3 h after dosing)
`
`89 (3 h after dosing)
`11 (3 h after dosing)
`20 (3 h after dosing)
`
`74
`—
`
`46
`11.5
`477
`—
`
`104
`22
`16
`—
`
`70
`44
`
`41
`11.1
`371
`48
`
`71 (after 150 mg/day reduction)
`22
`9
`11
`
`—
`—
`
`—
`—
`—
`—
`
`—
`—
`—
`—
`
`60 (8 h after last dosing)
`177
`—
`
`43 (2 h after last dosing)
`154
`—
`
`47 (8 h after last dosing)
`—
`17 (increased to 200 mg/day)
`
`Note. When sampling times after the last dosing differ between the blood samples, they are detailed after the result. Reference ranges used for the AEDs and their metabolites are as
`used by the Therapeutic Drug Monitoring Unit, National Hospital for Neurology and Neurosurgery, and based on published consensus [18]: 10-hydroxycarbazepine, 50–110;
`carbamazepine, b50; carbamazepine epoxide, b9; lacosamide, 40–80; lamotrigine, 4–60; levetiracetam, 45–118; phenytoin, b80; topiramate, 6–74.
`
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`J. Novy et al. / Epilepsy & Behavior 20 (2011) 20–23
`
`tolerated up to 100 mg/day, but he could not increase the dose further
`as he developed blurred vision, dizzy spells, and decreased alertness.
`These started typically half an hour after drug intake and lasted up
`to 2 hours. Carbamazepine levels did not change significantly and
`lacosamide was below the reference range. As the response was
`encouraging (he had not had any generalized seizures since starting
`lacosamide), carbamazepine was decreased to 1200 mg/day, leading
`to symptom resolution. Lacosamide was increased to 200 mg/day
`without recurrence of the symptoms. He continued to show signif-
`icant improvement in seizure frequency.
`
`2.3. Case 3
`
`This woman was admitted for seizure control as she was having
`several disabling seizures a week. She was on phenytoin 375 mg,
`lamotrigine 500 mg, rufinamide 1000 mg, and clonazepam 2 mg daily.
`Rufinamide was tapered and lacosamide started and increased up
`to 200 mg over 4 weeks. At this stage, she developed marked
`unsteadiness and diplopia about 2 hours after taking her medication.
`Lamotrigine reduction to 450 mg/day led to a marginal improvement
`in the dizziness. Serum levels 1 week after lamotrigine reduction
`showed a phenytoin level above the reference range, as previously, a
`lamotrigine level within the reference range, and a lacosamide level
`below the reference range. Phenytoin was decreased to 325 mg/day.
`Three weeks later, serum levels showed a small decrease in the phe-
`nytoin level, though still higher than the upper limit of the reference
`range. There were no significant changes in serum levels of the other
`AEDs. This last change reduced the symptoms and she had a slight
`decrease in seizure frequency.
`
`2.4. Case 4
`
`This woman had daily seizures on oxcarbazepine (750 mg daily)
`when she started lacosamide. When she reached 300 mg/day in two
`divided doses, she experienced severe diplopia, mostly after her evening
`medication. The serum 10-hydroxycarbazepine level did not show
`significant changes; lacosamide was within the reference range. As
`there was a significant decrease in seizure frequency, oxcarbazepine
`was decreased to 600 mg/day which led to complete resolution of the
`symptoms; she reduced the oxcarbazepine dose further on her own to
`300 mg/day. On this combination, she did well and had a significant
`decrease in seizure frequency.
`
`2.5. Case 5
`
`On carbamazepine 900 mg and levetiracetam 3000 mg daily, this
`woman was having several seizures per week. Lacosamide was started
`and slowly increased, leading to a significant decrease in seizures, but
`when she reached 350 mg/day, 4 months later, she developed severe
`drowsiness in the morning after drug intake. Her morning carbama-
`zepine dose was reduced to 100 mg (previously 300 mg), which
`improved the sleepiness but she remained unsteady and dysarthric.
`Her serum levels did not show any major changes; lacosamide level
`was within the reference range. Further reduction of carbamazepine
`led to resolution of symptoms.
`
`2.6. Case 6
`
`On phenytoin (150 mg), oxcarbazepine (1350 mg), and topiramate
`(250 mg) daily, this woman was continuing to have several seizures
`per week and was admitted for evaluation and drug changes. She was
`started on lacosamide. After 2 weeks when she reached 100 mg/day,
`she developed diplopia and unsteadiness. Oxcarbazepine was de-
`creased by 150 mg to 1200 mg/day which led to only a minimum
`improvement in symptoms. One week later, symptoms continued:
`serum levels showed a slightly decreased 10-hydroxycarbazepine
`
`level and no significant changes in topiramate and phenytoin levels;
`the lacosamide level was below the reference range. Oxcarbazepine
`was reduced gradually over 3 weeks to 300 mg daily which alleviated
`the symptoms and allowed concomitant increase in lacosamide up to
`200 mg daily. A mild reduction in seizure frequency was observed
`during her stay.
`
`2.7. Case 7
`
`This woman with weekly seizures was admitted for drug changes
`on clonazepam (1.5 mg daily), oxcarbazepine (1500 mg), diazepam
`(4 mg), and levetiracetam (4000 mg). She started on lacosamide and
`when she reached 100 mg/day, 2 weeks later, she developed diplopia,
`ataxia, and vertigo. Serum levels did not show major changes despite
`collection of blood at different times; lacosamide was not measured at
`that time but was below the reference range 1 month later while she
`was on 200 mg/day. As she had a reduction in seizures, oxcarbazepine
`was decreased to 1200 mg/day and the symptoms resolved; the 10-
`hydroxycarbazepine level showed a small fall. Lacosamide was further
`increased to 200 mg without any side effects and she continued to
`experience a favorable response to the treatment.
`In the same clinics, we identified six additional people with
`neurotoxicity on lacosamide who were not taking VGSC-blocking
`AEDs. We calculated the total drug load for all people according to
`Deckers et al. [12] (sum of the ratio of prescribed daily dose and usual
`daily dose defined by the World Health Organization). At the time of
`symptoms, the mean value was 2.9 (range: 0.5–6.6) for the 37 people
`for whom there were sufficient data and who were on lacosamide
`and another VGSC-blocking AED and 2.3 (range: 1.6–2.9) for the 6
`individuals on lacosamide without any other VGSC-blocking AED
`(P=0.41, Kruskal–Wallis test; SPSS Version 18). For the seven cases
`described above, the mean drug load was 3.3 and the mean change in
`drug load to alleviate the symptoms was 0.24 (range: 0–0.7).
`
`3. Discussion
`
`We report a series of seven people with refractory epilepsy who
`experienced significant central nervous system side effects (mostly
`dizziness, imbalance, diplopia, and sedation) on the introduction of
`lacosamide in combination with other VGSC-blocking AEDs. In some,
`the symptoms occurred shortly after drug intake (0.5–2 hours),
`compatible with peak serum levels. These symptoms occurred as
`lacosamide was at a low to medium dose (100–350 mg daily) and
`lacosamide levels were below or at the lower limit of the reference
`range. As previously reported [5,6], we did not find any convincing
`pharmacokinetic interaction, with no significant changes in concen-
`trations of concomitant AEDs. Reduction of the load of VGSC-blocking
`AEDs seemed to alleviate the symptoms, allowing further titration of
`lacosamide, which may suggest a pharmacodynamic interaction. Such
`an interaction was not found in a study involving healthy volunteers,
`perhaps because the combination of drugs was used only shortly
`(1 week) [6]. We cannot completely exclude a drug load effect in
`these people; however, their symptoms (such as diplopia) were
`suggestive of VGSC-blocking AEDs and not typical of other concom-
`itant AEDs such as levetiracetam and topiramate. As reported
`previously [10], we found that a larger number of people experienced
`neurotoxicity when lacosamide was added to another VGSC-blocking
`AED than when it was added to a non-VGSC-blocking AED (39 people
`vs 6 people). The comparison of drug load among people on
`lacosamide and another VGSC-blocking AED as compared with six
`controls (on lacosamide with non-VGSC-blocking AEDs) was not
`conclusive, probably owing to the small number of controls. In the
`seven individuals described, the drug load change to alleviate their
`symptoms was small (–0.24) and none had to discontinue any of their
`drugs. Two people (cases 1 and 7) did not require a decrease in their
`drug load, which makes an overall drug load effect less likely. In some
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`23
`
`of the 38 other people (on other VGSC-blocking AEDs or non-VGSC-
`blocking AEDs) experiencing neurotoxicity, a reduction in the
`concomitant AEDs did not alleviate the symptoms and lacosamide
`had to be reduced or stopped, which might suggest that the seven
`people discussed here experienced a specific interaction.
`The mechanism of this possible interaction might be explained by the
`common target (VGSC) of lacosamide, carbamazepine, oxcarbazepine,
`lamotrigine, and phenytoin. Lacosamide selectively enhances entry of
`VGSC into the unavailable slow-inactivated state (physiologically
`triggered by prolonged membrane depolarization), in contrast to con-
`ventional VGSC-blocking AEDs which act by enhancing fast inactivation
`[7]. On the basis of their in vitro properties, no interaction between
`lacosamide and the other VGSC-blocking AEDs was foreseen [7]. In fact,
`the binding site of carbamazepine and phenytoin on the VGSC is better
`known [13,14] than that of lacosamide, about which it is only known that
`it weakly displaces batrachotoxin from its binding site [15]. Recently, it
`was suggested that its action on the VGSC might be indirectly mediated
`through binding to CRMP-2 [9]. VGSC in the slow inactivation state
`(enhanced by lacosamide), however, has been shown to undergo a
`conformational change of its outer ring [16]. One explanation for this
`interaction might thus be that the conformational shift favored by
`lacosamide leads to increased VGSC affinity for binding other AEDs.
`Supporting this hypothesis, in rat dorsal root ganglion cells, blockade of
`sodium current mediated by carbamazepine was shown to be increased
`by the proportion of VGSC in the slow inactivated state. It was
`hypothesized that the drug might bind to a high-affinity site on the
`slow inactivated VGSC [17]. In the same experiment, carbamazepine was
`also shown to slow the return of the VGSC from the slow inactivated
`state to a normal available state, which might enhance the effects of
`lacosamide. VGSCs might become more sensitive to VSGC-blocking AEDs
`because of the effects of lacosamide, such that a subsequent reduction
`of the concomitant VGSC-blocking AED might restore the previous
`binding rate and improve tolerability. This would also explain why we
`did not observe any increase in seizure frequency after reduction of the
`concomitant VGSC-blocking AED. In our series, the combination of
`lacosamide with another VGSC-blocking AED was successful in reducing
`seizures, but our series was small and selected. Indeed, the reduction of
`the other VGSC-blocking AED was attempted as lacosamide had proven
`efficacious, but had this not been the case, lacosamide would have been
`stopped because of these side effects, without data on a potential
`pharmacodynamic interaction.
`This interaction could be demonstrated at least in 17.9% of people
`reporting neurotoxicity with the co-prescription of lacosamide and
`other VGSC-blocking AEDs. Two other people with symptoms also
`suggestive of this interaction were excluded as a pharmacokinetic
`interaction could not be excluded. Our series consisted of people who
`had an early encouraging response to the treatment, suggesting that
`the real prevalence of this interaction might be greater than suggested
`here.
`From a practical perspective, a stepwise progressive reduction in
`carbamazepine, oxcarbazepine, phenytoin, or lamotrigine (as needed)
`could be part of the regime for people starting lacosamide in
`association with these AEDs; as in our patients, a moderate reduc-
`tion (13–55% of the total dosage) was able to relieve symptoms.
`Alternatively, this could be undertaken when symptoms occur and
`lacosamide has been shown to be effective. In our series, some patients
`were then able to increase lacosamide further without recurrence of
`the side effects, whereas others needed further reduction of the other
`AED along with an increase in lacosamide. The use of such titration
`
`might improve lacosamide tolerability. This titration might thus help
`to avoid inappropriate withdrawal of a useful drug because of
`perceived lacosamide-related side effects. Our data suggest that the
`early appearance of neurotoxicity during the introduction of lacosa-
`mide with another VGSC-blocking AED may possibly be caused by a
`pharmacodynamic interaction. The frequency of this interaction is
`probably higher than demonstrated here (17.9%), but may be mostly
`encountered in people responding to lacosamide in clinical practice.
`
`Acknowledgments
`
`This work was undertaken at UCLH/UCL, which received a
`proportion of funding from the Department of Health's NIHR Biomedical
`Research Centres funding scheme. Dr. Novy is supported by the Swiss
`National Science Foundation Fellowships for Prospective Researchers.
`
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