Levetiracetam as Adjuvant Therapy

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Levetiracetam as Adjuvant Therapy
  OPEN ACCESS Full open access to this and thousands of other papers at Journal of Central Nervous System Disease  2011:3 17–25doi: 10.4137/JCNSD.S4126This article is available from© the author(s), publisher and licensee Libertas Academica Ltd.This is an open access article. Unrestricted non-commercial use is permitted provided the srcinal work is properly cited. Journal of Central Nervous System Disease REVIEW Journal of Central Nervous System Disease 2011:3 17 Levetiracetam Extended Release as Adjuvant Therapy for the Control of Partial-onset Seizures Hasan H. Sonmezturk and Nabil J. Azar  Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.Corresponding author email: Abstract: Extended release (XR) formulation of levetiracetam (LEV) is approved by the Food and Drug Administration as an add-on to other antiepileptic drugs (AEDs) for adults with partial onset seizures. This is based on class-I evidence demonstrating signicant seizure reduction in once daily dosing. Keppra-XR is marketed with the brand name of Keppra XR since 2008 (UCB Pharma). Its srci-nal immediate release (IR) formulation has been in the market since 2000. LEV has a unique molecular structure which is chemically unrelated to existing AEDs. The precise mechanism of action is unknown. Animal studies showed binding to synaptic vesicle protein SV2A, thought to be involved in modulating synaptic neurotransmitter release. LEV-IR is proven effective as adjunctive therapy for  partial-onset seizures, primary generalized tonic-clonic seizures and myoclonic seizures. It was shown to be equivalent to carbam- azepine as rst-line treatment for partial-onset seizures. The extended release formulation added advantages such as better tolerance and increased compliance. Keywords:  levetiracetam, extended release, partial-onset seizures  Sonmezturk and Azar  18 Journal of Central Nervous System Disease 2011:3 Introduction Epilepsy is a chronic condition characterized by recurrent unprovoked epileptic seizures. 1  It affects 0.5%–1% of the population and at least 50% of patients with epilepsy have partial seizures. About 30%–70% of partial seizures are controllable with antiepileptic drugs (AEDs). The majority of these patients will need lifelong AED therapy. Strict AED compliance is often related to better tolerability and is a key fac-tor in achieving better seizure control. An inverse relationship between the number of daily doses and compliance has been reported. Every increase in dosing frequency (from one to four doses per day) resulted in progressively worsening compliance and increased missed doses. 2–4  Conceptually, the stable  plasma concentration prole of extended release AED formulations is expected to minimize peak concentration–related adverse events and improve compliance and seizure control. 5,6  Extended release formulations may contribute to better tolerability and improved efcacy. 6  Extended release levetiracetam (LEV-XR) was developed to provide patients with the convenience of once-daily dosing, potentially improving compliance and the efcacy–tolerability ratio. It is shown that the pharmacokinetic prole for LEV-XR is comparable to immediate release levetiracetam (LEV-IR). 6,7  While both LEV-XR and LEV-IR formulations may cause similar side effects that are generally well-tolerated, LEV-XR is usually  preferred for its ease of use and more stable serum drug levels, both increasing patient compliance. The ease of conversion between LEV formulations also makes LEV-XR an attractive option. 8 Mechanism of Action, Metabolism and Pharmacokinetic P rofle Mechanism of action LEV-XR and LEV-IR have the same mechanism of action since the active molecule in these two formula-tions is the same. Despite much progress, the precise mechanism of action of LEV is still unknown. So far, the evidence supports a unique mechanism of action unlike any other known AED. 1,9,10  LEV does not have a known effect in common animal models of epilepsy, except in the chronic kindling models. 1,11,12  LEV doesn’t act through the three classic routes of other AEDs being sodium channel modulation, low-voltage-activated (T-type) calcium channel mod-ulation, or direct gamma-aminobutyric acid (GABA) facilitation. 8  It also does not share a high afnity to several known targets for existing AEDs including  phenytoin, carbamazepine, sodium valproate, pheno- barbital, dimethadione or benzodiazepines. 8,9  Lynch et al showed a saturable and stereoselective neuronal  binding site for LEV in rat brain tissue. The experi-mental data indicated that this binding site is a synap-tic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis and neurotrans-mitter release. 10  Although the molecular signicance of LEV binding to synaptic vesicle protein SV2A is not completely understood, LEV and related analogs showed a rank order of afnity for SV2A which cor  -related with the potency of their anti-seizure activity in audiogenic seizure-prone mice. 10  Similar ndings were noted in the mouse corneal kindling model and the GAERS rat model of generalized absence epilepsy. 1,13  SV2A protein was shown to have a size of about 90 kDa and to be ubiquitous throughout the central nervous system. 8,10  SV2A is thought to be involved in the physiologic functioning of the vesicle. 10  Crowder et al demonstrated seizures in SV2A knockout mice soon after birth which resulted in death of the mice at three weeks of age. 14  In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that LEV inhibits burst ring without affecting normal neuronal excitability, suggesting that LEV may selectively prevent hyper- synchronization of epileptiform burst ring and prop -agation of seizure activity. 15 Metabolism and pharmacokinetics The package insert drug information for Keppra XR UCB Pharma, Inc, described LEV-XR as 500 mg and 750 mg (white) extended-release tablets for oral administration. The chemical name of LEV, a single enantiomer, is (-)-(S)- α -ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C8H14N2O2 and its molecular weight is 170.21. LEV is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). LEV-XR tablets contain the labeled amount of LEV. Inactive ingredients include: colloidal anhydrous silica, hypromellose, magnesium stearate, polyethylene glycol 6000, polyvinyl alcohol-partially hydrolyzed, titanium dioxide and talc.  Levetiracetam XR in partial-onset seizures Journal of Central Nervous System Disease 2011:3 19 Bioavailability of LEV-XR tablets is similar to that of the LEV-IR tablets. 7  Its pharmacokinetics were shown to be dose proportional after single dose administration of 1000 mg, 2000 mg, and 3000 mgs. 7  LEV-XR is almost completely absorbed after oral administration. The pharmacokinetics of LEV-XR are linear and time-invariant, with low intra- and inter-subject variability. 7  LEV is not signicantly protein-  bound ( , 10% bound) and its volume of distribution is close to the volume of intracellular and extracellu-lar water. 16,17  Sixty-six percent of the dose is renally excreted unchanged. The mechanism of excretion is glomerular ltration with subsequent partial tubular reabsorption. The major metabolic pathway of LEV (24% of dose) is through an enzymatic hydrolysis of its acetamide group. Its metabolism is not through the cytochrome P450 system of liver. 6  The metabolites have no known pharmacological activity and are renally excreted. 6  Plasma half-life of LEV across studies is approximately 6–8 hours. This half-life is increased in the elderly (primarily due to impaired renal clearance) and in subjects with renal impairment. 18,19  LEV-XR peak plasma concentrations occur in about 4 hours. The time to peak plasma con-centrations is about 3 hours longer with LEV-XR than with LEV-IR. 7  Compared to 500 mg LEV-IR tablet twice daily, single administration of two 500 mg LEV-XR tablets once daily produced comparable maximal plasma concentrations. 7  Cmax and Cmin were lower by 17% and 26% after multiple dose LEV-XR tablets intake in comparison to multiple dose LEV-IR tablets intake. 7  Intake of a high fat or high calorie breakfast before the administration of LEV-XR tablets resulted in a higher peak concentra-tion, and longer median time to peak. The median time to peak (Tmax) was 2 hours longer in the fed state. 16,17  Single administrations of two 750 mg LEV-XR tablets and three 500 mg LEV-XR tablets were equivalent to each other. 7  In vitro data on meta- bolic interactions indicate that LEV is unlikely to  produce, or be subject to, pharmacokinetic interactions. 16,17  LEV and its major metabolite, at con-centrations well above Cmax levels achieved within the therapeutic dose range, are not inhibitors and do not exhibit high afnity to human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuroni-dation enzymes. 16,17  In addition, LEV does not affect the in vitro glucuronidation of valproic acid. LEV and its major metabolite are less than 10% bound to  plasma proteins; rendering interactions with other drugs through competition for protein binding sites unlikely. 16,17  The potential for drug interactions for LEV-XR is expected to be similar to that with LEV-IR. Clinical Studies Pivotal studies for LEV-IR Three major randomized placebo-controlled blinded clinical trials were conducted for LEV-IR efcacy in adults with refractory partial epilepsy. One of these tri-als was conducted in the US 20  and the remaining two studies were conducted in Europe. 21,22  LEV-IR was found to be efcacious in all three of these studies. 1  Three doses of 1000, 2000, and 3000 mg/day were studied and all were found to be efcacious. 1,20–22 The US trial by Cereghino et al compared LEV-IR 1000 mg/day (500 mg bid) and 3000 mg/day (1500 mg bid) with placebo 20  in adult patients 16 to 70 years of age with drug resistant partial onset sei-zures (refractory to at least 2 AEDs). A total of 294  patients were randomized, of whom 268 completed the 14 weeks of treatment. After an initial 12-week single-blind baseline, LEV-IR was titrated over four weeks. Patients in the 1000 mg/day group rst received 333 mg/day for 2 weeks then 666 mg/day for 2 weeks. Patients in the 3000 mg/day group received 1000 mg/day for 2 weeks and then 2000 mg/day for 2 weeks. The median percentage reduction in seizures over baseline was 32.5% for LEV-IR 1000 mg/day and 37.1% with LEV-IR 3000 mg/day, and 6.8% with placebo (  P ,  0.001). The median percent reduction in seizure frequency over placebo was 20.9% with LEV-IR 1000 mg/day (  P ,  0.001) and 27.7% with LEV-IR 3000 mg/day (  P ,  0.001). The responder rate was 33% with LEV-IR 1000 mg/day, 39.8% with LEV-IR 3000 mg/day, and 10.8% with placebo (  P ,  0.001). Eight patients in the LEV-IR 3000 mg/day group were seizure-free during the entire 14-week evalua-tion period compared to none in the placebo group (  P =  0.01).One of the European trials by Shorvon et al evalu- ated the efcacy and tolerability of LEV-IR 1000 mg/day (500 mg bid) and 2000 mg/day (1000 mg  bid) and placebo as add-on therapy in adult patients with drug-resistant partial-onset seizures (refractory  Sonmezturk and Azar  20 Journal of Central Nervous System Disease 2011:3 to 1 to 2 AEDs). 21  The study consisted of an 8-week  baseline period followed by 4-week titration period. The LEV-IR 1000 mg/day group received placebo for 2 weeks followed by 500 mg bid of LEV-IR. The LEV-IR 2000 mg/day group received 500 mg bid for 2 weeks followed by 1000 mg bid. The 4-week titration period was followed by a 12-week mainte-nance period. A total of 324 patients were randomized and 278 completed the study. There were 112 patients in the placebo group, 106 in the LEV-IR 1000 mg/day group, and 106 in the LEV-IR 2000 mg/day group. There was a 26.5% median seizure reduction from  baseline for the LEV-IR 2000 mg/day group (  P ,  0.001), 17.7% median seizure reduction for the LEV-IR 1000 mg/day group (  P ,  0.001) and 10.4% median seizure reduction for the placebo group. Two  percent of the LEV-IR 2000 mg/day group, 5% of the LEV-IR 1000 mg/day group and 1% of the placebo group were seizure free. The responder rate was 22.8% with LEV-IR 1000 mg/day (  P ,  0.02), 31.6% with LEV-IR 2000 mg/day (  P ,  0.001), and 10.4% with placebo.Another European trial by Ben-Menachem and Falter, compared LEV-IR 3000 mg/day and placebo as add-on therapy in patients 16 to 70 years of age with drug-resistant partial-onset seizures. 22  The study con-sisted of 12-week baseline period followed by a 4-week titration and 14-week maintenance period for add-on  part of the study. This was followed by a 12-week monotherapy phase after a 12-week taper period of additional AEDs. Patients initially received LEV-IR 1000 mg/day for 2 weeks, then 2000 mg/day for 2 weeks and then 3000 mg/day for the remainder of the trial. The monotherapy phase included patients who responded very well to LEV-IR and who received 3000 mg/day. A total of 286 patients were randomized, 181 to LEV-IR and 105 to placebo. Of this intention-to-treat population, 19.9% of patients in the LEV-IR group completed the study in comparison to 9.5% in the pla-cebo group (  P =  0.029). In reference to the add-on  phase, the median percent reduction in seizure fre-quency from baseline was 39.9% with LEV-IR and 7.2% with placebo (  P ,  0.001). The responder rate was 42.1% with LEV-IR and 16.7% with placebo (  P ,  0.001). Fourteen patients in the LEV-IR group (8.2%) remained seizure-free during the add-on evaluation period and one in the placebo group (  P =  0.012). Eighty-six patients out of 239 were continued into the monotherapy phase (69 patients on LEV-IR, and 17 patients on placebo). Out of the 69 LEV-IR treated patients, 49 were successfully tapered to monotherapy and 36 (19.9%) completed the study. Only 10 patients in the placebo group completed the study and 4 of them switched to LEV-IR but remained in the placebo group. In the LEV-IR group the median percent seizure reduction from baseline during the monotherapy phase was 73.8%, responder rate was 59.2% and 9 patients out of 49 became seizure free. Other LEV-IR studies Brodie et al compared LEV-IR to controlled-release carbamazepine (CBZ-CR) in adult patients with newly diagnosed epilepsy. 23  This was a large multicenter, double-blind trial which compared the efcacy and tolerability of these two AEDs. To enter the study,  patients had to have two or more partial or generalized tonic-clonic seizures in the previous year. After ran-domization, patients were randomized to either LEV-IR 500 mg bid (n =  285) or CBZ-CR 200 mg bid (n =  291). The doses could be titrated up to 1500 mg  bid for LEV-IR and 600 mg bid for CBZ-CR if patients had further seizures. At six months, 73% of LEV-IR and 72.8% of CBZ-CR patients were seizure free. At one year 56.6% of LEV-IR and 58.5% of CBZ-CR  patients were seizure free. There was a trend towards higher withdrawal rates due to adverse events in the CBZ-CR group (19.2%) when compared to the LEV group (14.4%); however, this was not statistically sig- nicant. This study demonstrated that LEV-IR had similar efcacy as CBZ-CR but lower adverse effects. This trial formed the basis of granting LEV-IR an indi-cation for monotherapy in newly diagnosed epilepsy  patients in the European Union. LEV-IR does not have FDA approval for the same indication in the US.LEV-IR received FDA approval as an add-on therapy for refractory partial-onset seizures in pedi-atric patients (4 to 16 years of age) based on a double-blind, placebo controlled, multicenter trial. 24  In this study, 216 patients were randomized and 198 patients provided sufcient data. The goal dose was 60 mg/kg/day in two divided doses. This dose was reached in three steps. The initial dose was 20 mg/kg/day for two weeks then 40 mg/kg/day for two weeks and then 60 mg/kg/day. The goal dose

Chapter 7

Jul 23, 2017
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