Levetiracetam Intravenous Infusion: A Randomized, Placebo-controlled Safety and Pharmacokinetic Study

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1 Epilepsia, 47(7): , 2006 Blackwell Publishing, Inc. C 2006 International League Against Epilepsy Levetiracetam Intravenous Infusion: A Randomized, Placebo-controlled Safety and Pharmacokinetic Study Steven Ramael, Agnès Daoust, Christian Otoul, Nathalie Toublanc, Mona Troenaru, Zhihong (Sarah) Lu, and Armel Stockis SGS Life Sciences Services, Research Unit, Stuivenberg Hospital, Antwerp, Belgium; UCB Pharma SA, Nanterre, France; UCB S.A., Braine l Alleud, Belgium; and UCB Pharma, Inc., Smyrna, Georgia, U.S.A. Summary: Purpose: The primary objective of this placebocontrolled study was to evaluate the safety and tolerability of levetiracetam (LEV) administered intravenously (IV) at higher doses and/or at a faster infusion rate than proposed. The secondary objective was to assess LEV pharmacokinetics. Methods: Single ascending doses of LEV administered by IV infusion (2,000, 3,000, 4,000 mg over 15 min; 1,500, 2,000, 2,500 mg over 5 min) were evaluated in 48 healthy subjects in a randomized, single-blind, placebo-controlled study. Results: All randomized subjects completed the study. Adverse events reported after IV administration of LEV ( 4,000 mg infused over 15 min and 2,500 mg infused over 5 min) were primarily related to the CNS (dizziness, 52.8%; somnolence, 33.3%; fatigue, 11.1%; headache, 8.3%) and were consistent with the established safety profile for the oral formulation. Safety profiles were similar for each dose level of LEV and for both IV infusion rates, with no clear relation noted between incidence of adverse events and IV dose level or infusion rate. The pharmacokinetics of LEV administered by IV infusion was comparable across all dose groups and infusion rates. Respective geometric means (coefficient of variation) for 4,000 mg administered over 15 min and 2,500 mg infused over 5 min were maximum plasma concentration, 145 (24.6%) and 94.3 (36.2%) μg/ml; area under the plasma concentration time curve, 1,239 (19.2%) and 585 (9.6%) μg/h/ml; terminal half-life, 8.0 (14.5%) and 7.0 (12.7%) h. Conclusions: LEV administered by IV infusion at dosages and/or infusion rates higher than those proposed was well tolerated in healthy subjects, and the pharmacokinetic profile was consistent with that for LEV administered orally. Key Words: Epilepsy Intravenous infusion Levetiracetam Pharmacokinetics Safety. Levetiracetam (LEV; Keppra) is a new antiepileptic drug (AED) prescribed worldwide as adjunctive treatment for partial-onset seizures in adults and children aged 4 years and older. Recently, the synaptic vesicle protein 2A (SV2A) was identified as the binding site of LEV in the brain (1). The mechanism of action of levetiracetam appears to be distinct from that of classic AEDs and unrelated to known mechanisms of neurotransmission. It has been shown partially to inhibit N-type high-voltage activated Ca 2+ currents (2 5) and diminishes the effects of negative allosteric modulators on the two main inhibitory ionotropic receptor systems, γ -aminobutyric acid (GABA) and glycine-gated currents (6). The efficacy and safety of oral LEV have been well established in double-blind, placebo-controlled clinical tri- Accepted February 24, Address correspondence and reprint requests to Dr. S. Ramael at SGS Life Sciences Services, Research Unit Stuivenberg Hospital, Lange Beeldekensstraat 267, B-2-60 Antwerp, Belgium. steven.ramael@sgs.com doi: /j x als (7 10) and open-label studies (11,12). Patients treated with oral LEV for refractory partial epilepsy experienced significant reductions in seizure frequency (7 10). Evidence of a rapid onset of action of LEV, 1,000 mg, was recently demonstrated through a significant increase in the proportion of seizure-free patients as of the first day of treatment (13). It has been shown that LEV efficacy is sustained over the long term, with no indication of the development of tolerance to its anticonvulsant effects (14). Continuation or retention rates were similar to or better than those reported for other new AEDs (lamotrigine, vigabatrin, gabapentin, and topiramate) (15). Because epilepsy requires long-term AED treatment, an injectable formulation is an important treatment option for patients who are temporarily unable to take an oral dosage form. The injectable LEV formulation was developed for intravenous (IV) use in epilepsy patients with partial-onset seizures, when oral administration is temporarily not feasible. A recent study showed that the injectable formulation of LEV administered IV (1,500 mg infused over 15 min) is bioequivalent with 1,500 mg given as three 500-mg oral tablets and is well tolerated in healthy subjects (16). The 1128

2 LEVETIRACETAM INTRAVENOUS INFUSION 1129 proposed single dose of LEV injectable is 500 to 1,500 mg diluted in 100 ml of compatible diluent 0.9% saline or 0.5% dextrose solutions and administered as a 15-min IV infusion. The primary objective of the present study was to evaluate the safety and tolerability of several doses of LEV administered IV at various infusion rates. The secondary objective was to assess the pharmacokinetics of LEV IV administration in the dosing regimens tested. METHODS The study was a phase I, randomized, single-blind, single-ascending-dose, placebo-controlled trial conducted at Stuivenberg Hospital, SGS LSS Clinical Research Unit, Antwerp, Belgium. Each dose of LEV was administered as a single IV infusion. Dosages of LEV studied were 2,000, 3,000, and 4,000 mg administered as an infusion over 15 min and 1,500, 2,000, and 2,500 mg administered as an infusion over 5 min. For each dosage, six subjects (three male, three female patients) received the randomized LEV dosage, and two (one male, one female patient) received placebo. The study protocol was approved by the Commissie voor Medische Ethiek ZNA/O.C.M.W., the ethics committee for the public hospitals of the city of Antwerp (Belgium). All subjects gave written informed consent before participation. Study population Healthy subjects aged 18 to 55 years were recruited for the study. Subjects had to be in a good physical and mental health status, to have a body mass index between 19 and 28 kg/m 2, and to have given their written informed consent to participate in the study. Women were either without childbearing potential or had a negative pregnancy test at screening and were using a medically accepted method of contraception for the duration of the study. Subjects were excluded if they had any disorders that could alter drug pharmacokinetics or constitute a risk factor when taking the study medication, including a known allergy/intolerance to pyrrolidone derivatives or to other excipients or diluents that were components of the LEV injectable formulation. Subjects could withdraw from the study at any time. The investigator was allowed to withdraw a subject for reasons of medical prudence (safety) or protocol deviation that could invalidate interpretation of the results. Posttrial procedures were performed whenever possible on any subjects who withdrew. Study treatment Patients were given a unique sequential randomization number generated by a validated computer program provided by the UCB Biostatistics Department. Each study participant was assigned a treatment number, to which the investigator was blinded. Participants were randomized, with randomization stratified by gender (1:1), to one of six LEV treatment groups: 2,000, 3,000, or 4,000 mg administered IV over 15 min; or 1,500, 2,000, or 2,500 mg administered IV over 5 min or placebo. As the descriptive portion of this study did not have to be statistically powered (no hypothesis-testing objective was stated), it was deemed that six LEV-treated and two placebo-treated subjects (half male and half female patients) per dose group were sufficient. Each LEV dose was diluted in 100 ml of normal saline and administered in the morning after an overnight fast of 10 h. Dose selection was based on clinical experience with oral LEV. Oral doses between 500 mg and 1,500 mg dosed twice daily have been shown significantly to reduce seizure frequency and are generally well tolerated (7,9,10). To document the safety and tolerability of LEV administered IV and to understand the consequences of any potential dosing errors, the doses and rates of infusion evaluated in this study were higher than the proposed maximal daily dose and rate of infusion. Infusion rates varied between 480 and 560 ml/h for the 15-min infusion and as high as 1,380 and 1,500 ml/h for the 5-min infusion. This extremely high infusion rate was achieved by placing two infusion pumps in parallel at rates varying from 690 to 750 ml/h. The only concomitant medications allowed within 2 weeks of administration of study drug were hormonal contraceptives; hormone-replacement therapy; and paracetamol (acetaminophen), not exceeding 2 g/day up to a total of 10 g/14 days. No drugs except those mentioned were allowed during the study treatment period unless required to treat an adverse event. Subjects were not allowed to smoke or ingest alcohol or food or beverages containing caffeine, beginning 24 h before administration of study drug through completion of all study procedures. Safety assessments Safety assessments included monitoring for adverse events, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory testing (hematology, biochemistry, glycemia, urinalysis). Subjects were confined in the clinical center and under medical supervision for 24 h after the dose or longer, as deemed necessary. Trial participants reported adverse events spontaneously. A general prompt was also given by the investigator at regular intervals to detect adverse events and changes in the subject s well-being. All adverse events occurring in the pretreatment, treatment, and posttreatment periods were recorded. Each adverse event was characterized as to intensity, causal relation to study drug, seriousness, action taken, and outcome. A physical examination and clinical laboratory testing were done at screening and during the posttreatment period. Vital signs and ECGs were performed at screening; predose; at the end of the infusion; 15 and 30 min after the end of the infusion; 1 h,

3 1130 S. RAMAEL ET AL. 2 h, 12 h, and 24 h after the dose; and within 7 days after the last day of treatment. Pharmacokinetic analysis Blood samples (5 ml) were collected over lithium heparin, immediately before starting the infusion, and at time points of 5, 10, 15, and 30 min and 1, 2, 3, 6, 9, 12, and 24 h. The plasma was separated at 900 g for 15 min in a refrigerated centrifuge ( +4 C) within 30 min after sampling, and the samples were stored frozen at 20 C. Plasma LEV concentrations were determined by using a validated gas chromatographic method with a lower limit of quantification of 0.5 μg/ml (17). Each batch of assays included a full set of calibrator and six qualitycontrol samples. Pharmacokinetic parameters were calculated from individual plasma concentration time profiles of LEV obtained 24 h after the dose by using noncompartmental methods and included maximum plasma concentration (C max ), time to C max (t max ), plasma concentration at the end of the 15-min (C 15 ) or 5-min (C 5 ) infusion, area under the plasma concentration versus time curve from time 0 to last quantifiable concentration (AUC (0 t) ) and from time 0 to infinity (AUC), first-order terminal elimination rate constant (λ z ), terminal half-life (t 1/2 ), total body clearance (CL), and volume of distribution (V z ). Statistical methods For analyses of safety and tolerability, the six LEV groups were compared mainly descriptively with placebotreated subjects who were pooled to form one group of 12. Analyses were performed on the intent-to-treat (ITT) population (all randomized subjects who received study medication). Treatment-emergent adverse events were classified by preferred term (Medical Dictionary for Regulatory Activities, MedDRA) and primary System Organ Class as well as by severity and relation to study drug. The incidence of adverse events was compared between the LEV and placebo groups by using Fisher s exact test, and the dose effect relation was evaluated by using the Cochran- Armitage test (18). Changes from screening or predose in laboratory values, vital signs, and ECG results were assessed. Pharmacokinetic analyses were performed on the perprotocol population (subjects who had no major deviations from the protocol that would affect pharmacokinetic parameters). Plasma LEV concentrations were summarized by dose group by using descriptive statistics. Coefficients of variation and geometric means were determined for the computed pharmacokinetic parameters. AUC dose proportionality was assessed by analysis of variance and linear regression methods, by using the SAS PROC MIXED procedure. The following linear regression model, referenced as power model, was fitted: log e (AUC) = μ + β log e (Dose), where the estimate of β is a measure of dose proportionality (β = 1 for proportionality). The estimate of β and its 90% confidence interval (CI) were computed and compared with the acceptance range (19). RESULTS After medical screening procedures, 48 healthy subjects (24 men, 24 women) were randomized to either LEV (n = 36) or to placebo (n = 12), and all completed the study (which began on January 22, 2003, with the inclusion of the first subject and ended on March 8, 2003, with the completion of the trial of the last subject) and composed the ITT population for the safety analyses. The overall mean age of subjects was 37.8 ± 9.7 years (range, years). The demographic characteristics of subjects in the six LEV dose groups were comparable to those of the placebo group (Table 1). Safety In total, 34 (70.8%) subjects (31 of 36 LEV, three of 12 placebo) experienced at least one of the 64 reported treatment-emergent adverse events. There was a statistically significant effect of LEV IV (all doses combined) on the incidence of drug-related treatment-emergent adverse events (all and CNS related) as compared with the placebo group in this population of healthy volunteers. No statistically significant dose-related effect of LEV (dose range, 1, mg) could be detected, but a trend toward an increased incidence of adverse events with increasing doses of LEV was observed from 1,500 4,000 mg IV (all TABLE 1. Demographic characteristics for the 48 randomized subjects Levetiracetam IV, 15 min Levetiracetam IV, 5 min Placebo 2,000 mg 3,000 mg 4,000 mg 1,500 mg 2,000 mg 2,500 mg (n = 12) (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) Age, yr 37.8 ± ± ± ± ± ± ± 10.8 Weight, kg 71.3 ± ± ± ± ± ± ± 6.4 Height, cm ± ± ± ± ± ± ± 7.1 BMI, kg/m ± ± ± ± ± ± ± 1.7 BSA, m ± ± ± ± ± ± ± 0.11 Values are expressed as mean ± standard deviation. BMI, body mass index; BSA, body surface area; IV, intravenous.

4 LEVETIRACETAM INTRAVENOUS INFUSION 1131 TABLE 2. Number (percentage) of subjects with study drug-related, treatment-emergent adverse events, intent-to-treat population Levetiracetam intravenous infusion 15 min 5 min System organ class/ Placebo 2,000 mg 3,000 mg 4,000 mg 1,500 mg 2,000 mg 2,500 mg All levetiracetam doses preferred term (n = 12) (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) (n = 36) Any drug-related adverse events 1 (8.3) 4 (66.7) 5 (83.3) 6 (100) 5 (83.3) 3 (50) 6 (100) 29 (80.6) Nervous system 1 (8.3) 3 (50) 4 (66.7) 6 (100) 5 (83.3) 3 (50) 6 (100) 27 (75) Balance disorder (16.7) (2.8) Dizziness 0 2 (33.3) 1 (16.7) 5 (83.3) 4 (66.7) 2 (33.3) 5 (83.3) 19 (52.8) Dizziness postural (50) 1 (16.7) 1 (16.7) 2 (33.3) 0 7 (19.4) Dysgeusia 1 (8.3) Headache (16.7) 0 1 (16.7) 1 (16.7) 3 (8.3) Somnolence 0 1 (16.7) 1 (16.7) 2 (33.3) 2 (33.3) 3 (50) 3 (50) 12 (33.3) Eye, blurred vision (16.7) 1 (2.8) GI disorders (16.7) 0 1 (16.7) 0 2 (5.6) Dry mouth (16.7) 0 1 (2.8) Nausea (16.7) (2.8) Vomiting (16.7) (2.8) General disorders 0 1 (16.7) 2 (33.3) (16.7) 1 (16.7) 5 (13.9) Fatigue 0 1 (16.7) 2 (33.3) (16.7) 4 (11.1) Feeling drunk (16.7) (2.8) Thirst (16.7) 0 1 (2.8) GI, gastrointestinal. drug-related: p = 0.079; CNS drug-related: p = 0.100). However, no significant effect of the duration of infusion (5 min vs. 15 min) on the incidence of drug-related (all and CNS) treatment-emergent adverse events was observed. All drug-related adverse events occurred shortly after dosing. In general, the onset was within the first 4 h after the dose and up to a maximum of 1 day after the dose (one case of dizziness and one case of somnolence). Of the 54 drug-related adverse events, 21 (mostly dizziness and somnolence) started during the first hour after the dose. About 50% of these 21 drug-related adverse events had an onset during the infusion (mostly dizziness). They were all mild to moderate in intensity, short in duration, and resolved during the study. The majority lasted for 8 h, with a maximum duration of 1 day in two instances of mild somnolence and one case of dizziness and blurred vision. No deaths or other serious adverse events occurred, and none of the subjects discontinued the study because of an adverse event. No adverse events were related to the IV infusion procedure. For all doses of LEV IV combined, the most frequently reported study drug-related, treatment-emergent adverse events were associated with the CNS and included dizziness (52.8%), somnolence (33.3%), postural dizziness (19.4%), fatigue (11.1%), and headache (8.3%) (Table 2). No clinically significant findings or changes from baseline were noted in hematology, biochemistry, glycemia, urinalysis, laboratory test results, ECGs, or physical examination in any of the six LEV IV treatment groups and at any assessments (data not shown). Vital signs observed during the 24 h after the dose are summarized in Table 3. Similar to the placebo group, the mean changes in blood pressure and heart rate from predose during the 24 h after LEV IV infusion were low: the mean change varied from 2.7 to +0.8 mm Hg for systolic blood pressure, from 2.5 to +1.3 mm Hg for diastolic blood pressure, and 0.4 to +3.8 beats/min for heart rate. Changes were similar within each of the six dosing groups. Pharmacokinetics The per-protocol population for the pharmacokinetic analysis included 35 subjects who received LEV. One subject receiving LEV, 4,000 mg IV over 15 min, was excluded because of disconnection of the infusion line, which led to incomplete dosing. After both the 15- and 5- min IV infusions, plasma LEV concentrations increased rapidly during infusion and then decreased monoexponentially (Figs. 1 and 2, respectively). Table 4 presents the mean pharmacokinetic parameters for each LEV dose and infusion duration. For the 15-min infusion of the 2,000-, 3,000-, and 4,000- mg doses, the respective mean C max values were 55.6 μg/ml, 81.2 μg/ml, and 145 μg/ml. For the 5-min infusion of the 1,500-, 2,000-, and 2,500-mg doses, the respective mean C max values were 46.9 μg/ml, 60.6 μg/ml, and 94.3 μg/ml. All LEV CL, V z, and t 1/2 mean values were comparable across all dose groups (Table 4). The mean AUC increased proportionate to the dose from 1,500 mg to 3,000 mg (both infusion rates combined; dose proportionality coefficient β: 1.06; 90% CI, ). The mean dose-adjusted AUC observed in the 4,000-mg group, consisting of only five subjects, was 22% overproportional when compared with that at 2,000 mg. The intersubject

5 1132 S. RAMAEL ET AL. TABLE 3. Descriptive statistics for vital signs by treatment over time: baseline (predose) and change from predose after single IV dose of levetiracetam or placebo Mean change from predose at postdose time point Baseline 15 min after 30 min after (predose) End infusion end infusion end infusion 1 h 2 h 12 h 24 h Systolic blood pressure supine (mm Hg) Placebo (n = 12) Mean (± SD) (10.6) +2.5 (6.6) 1.8 (9.4) 1.5 (11.2) +0.9 (12.4) 1.8 (6.2) 1.8 (9.7) 0.8 (8.3) Range 97 to to to to to to to to +13 Levetiracetam (n = 35) a Mean ± SD (11.1) +0.8 (7.2) 0.4 (8.2) 1.2 (6.4) 0.7 (7.9) 1.3 (7.8) 0.4 (7.8) 2.7 (7.6) Range 91 to to to to to to to to +14 Diastolic blood pressure supine (mm Hg) Placebo (n = 12) Mean (± SD) 72.3 (9.1) +3.2 (4.9) +1.4 (3.8) +0.8 (7.8) +3.8 (9.3) +0.5 (6.6) 0.7 (2.3) +0.4 (5.0) Range 61 to 87 3 to+15 7 to+7 18 to to to to+3 7 to+ 9 Levetiracetam (n = 35) a Mean (± SD) 68.8 (8.4) +1.2 (7.5) +1.3 (7.0) +0.7 (5.9) +1.0 (5.3) +0.6 (6.5) +0.4 (7.8) 2.5 (7.3) Range 48 to to to to+18 8 to to to to +19 Heart rate supine (beats/min) Placebo (n = 12) Mean (± SD) 60.1 (10.3) +1.8 (5.4) +0.7 (5.3) 0.1 (3.5) +3.5 (6.4) +1.6 (5.3) +2.3 (9.4) +7.2 (9.7) Range 46 to 84 5 to+13 4 to+14 6 to+8 7 to+16 7 to+9 10 to to+29 Levetiracetam (n = 35) a Mean (SD) 59.5 (9.1) +3.4 (6.5) +1.6 (5.9) +0.8 (5.3) +0.6 (6.6) +2.5 (9.5) 0.4 (6.9) +3.8 (10.4) Range 43 to to to+23 9 to to to to to +38 a All levetiracetam doses and infusion durations. coefficient of variation was 12.9% and 32.5% for AUC and C max, respectively. DISCUSSION With its clinical profile established for oral dosage formulations (tablets, oral solution), an injectable formula- tion of LEV would provide clinicians greater flexibility in treating patients with partial-onset seizures. The proposed dosage of the injectable LEV formulation for IV administration (available as 5 ml of a solution containing 100 mg/ml) in adults is 500 1,500 mg diluted in 100 ml of compatible diluent administered as a 15-min infusion FIG. 1. Levetiracetam plasma concentration time profiles after a single 15-min intravenous infusion of 2,000 mg (n = 6), 3,000 mg (n = 6), or 4,000 mg (n = 5). Inset: Levetiracetam plasma concentrations in the 0- to 1-h interval. The results are expressed as geometric mean ± standard deviation.

6 LEVETIRACETAM INTRAVENOUS INFUSION 1133 FIG. 2. Levetiracetam plasma concentration time profiles after a single 5-min intravenous infusion of 1,500 mg, 2,000 mg, or 2,500 mg. Inset: Levetiracetam plasma concentrations in the 0- to 1-h interval. The results are expressed as geometric mean ± standard deviation; n = 6. twice daily, with a maximum recommended daily dose of 3,000 mg (same daily dose as recommended for the oral formulation). The results of this study demonstrated that LEV IV at dosages and/or infusion rates higher than those proposed (dosages 4,000 mg over 15 min and 2,500 mg over 5 min) was well tolerated in healthy subjects, and provided information on the safety margin of LEV IV. The observed adverse events were of mild or moderate intensity and resolved within 1 day. As previously observed for the oral dosage formulation (20), no clear relation was found between the incidence of adverse events and LEV IV dose or duration of infusion. For all doses of LEV IV combined, the most commonly reported drug-related adverse events were related to the CNS and included dizziness (52.8%), somnolence (33.3%), postural dizziness (19.4%), fatigue (11.1%), and headache (8.3%). In a study of LEV, 1,500 mg, infused in 15 min (16), similar incidences were observed for postural dizziness, headache, and somnolence, whereas dizziness and fatigue were infrequently observed. It is unclear whether the latter difference was related to the dose and infusion rate. The results are also consistent with another exploratory safety study of adjunctive LEV IV in patients with epilepsy who had switched from the oral TABLE 4. Pharmacokinetic parameters of levetiracetam after a single 15-min intravenous infusion of 2,000-mg, 3,000-mg, and 4,000-mg doses, and after a single 5-min intravenous infusion of 1,500-mg, 2,000-mg, and 2,500-mg doses, per protocol population 15-min intravenous infusion 5-min intravenous infusion 2,000 mg 3,000 mg 4,000 mg 1,500 mg 2,000 mg 2,500 mg Parameter (n = 6) (n = 6) (n = 5 a ) (n = 6) (n = 6) (n = 6) C max (μg/ml) 55.6 (25.7) 81.2 (44.9) 145 (24.6) 46.9 (18.0) 60.6 (40.0) 94.3 (36.2) C 15 or C 5 (μg/ml) 50.5 (35.9) 74.3 (55.9) 142 (27.4) 41.7 (21.9) 56.3 (45.4) 91.3 (37.4) t max (h) 0.50 ( ) ( ) 0.25 ( ) ( ) ( ) ( ) AUC 0 t (μg/h/ml) 470 (16.4) 665 (9.2) 1081 (19.1) 312 (5.8) 429 (13.7) 531 (10.1) AUC (μg/h/ml) 529 (16.3) 754 (6.4) 1239 (19.2) 348 (7.6) 484 (14.3) 585 (9.6) t 1/2 (h) 7.71 (11.1) 7.71 (13.1) 8.00 (14.5) 7.38 (12.4) 7.72 (12.6) 6.98 (12.7) CL (l/h) 3.78 (16.3) 3.98 (6.4) 3.23 (19.2) 4.32 (7.6) 4.13 (14.3) 4.28 (9.6) V z (l) 42.0 (18.4) 44.2 (17.7) 37.3 (22.9) 45.9 (8.4) 46.0 (16.5) 43.1 (16.2) Values are reported as geometric mean [coefficient of variation (%)], except for t max, which is expressed as median (range). AUC, area under the plasma concentration time curve from time 0 to infinity; AUC 0 t, area under the plasma concentration time curve from time 0 to last quantifiable concentration; C 15,orC 5, plasma concentration at the end of the 15-min or 5-min infusion; C max, maximum plasma concentration; CL, total body clearance; t max, time to maximum plasma concentration; t 1/2, terminal half-life; V z, volume of distribution. a One subject excluded from per-protocol population because of connection-line problem during the infusion.

7 1134 S. RAMAEL ET AL. to the IV route of administration (500 1,500 mg twice daily, 15-min infusion, 4.5 days) (21), and with the established adverse-event profile for adjunctive oral LEV in placebo-controlled phase II/III trials in patients with partial epilepsy (20,22). No clinically significant changes from baseline in clinical laboratory test results (hematology, biochemistry, urinalysis), vital signs, ECGs, or physical examinations were reported after LEV IV dosing, which is consistent with previously reported findings for the oral dosage formulations (20,23) and the injectable formulation (16). Thus the present study revealed no unexpected risks when LEV is administered as a single IV infusion at dosages and/or infusion rates higher than those proposed. The pharmacokinetic parameters (t 1/2, CL, and V z )of LEV determined in the present study were similar across all IV dose groups. They also were comparable to those previously reported for oral formulations of LEV, including tablets (24,25) and oral solution (26). Dose proportionality was shown with LEV IV, which is consistent with the linear pharmacokinetics established for oral (tablets) LEV (24,25,27).The similarity of the pharmacokinetic profile of LEV IV to that of the oral formulations (tablets, solution) and the bioequivalence of the LEV IV (16) and the oral solution (28) with the tablets suggest the potential for easy conversion from one pharmaceutical form to another, without the need for dose adjustments. The pharmacokinetic profile of LEV (linear pharmacokinetics, <10% plasma protein binding, metabolism not dependent on cytochrome P450 enzymes) provides relative ease of dosing and contributes to the low potential for pharmacokinetic drug interactions (24 27,29). LEV (oral tablets) does not affect the plasma concentration of concomitantly administered AEDs, digoxin, warfarin, or oral contraceptives (25,26,30 32) and appears to produce minimal risk with other medications that may be given before or after LEV IV. The pharmacokinetics of oral LEV is not affected in a clinically significant way by the concomitant administration of other AEDs (29), and it can be safely inferred that the pharmacokinetics of LEV IV should not be altered by other AEDs (17). The consistent pharmacokinetic and safety characteristics of LEV, in either an oral or injectable form, suggest that monitoring blood levels would be unnecessary. In conclusion, LEV administered by IV infusion at dosages and/or infusion rates higher than those proposed was well tolerated in healthy subjects, and the pharmacokinetic profile was consistent with that for oral LEV. 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