Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects

Clinical Therapeutics/Volume 28, Number 5, 2006

Single-Dose Bioavailability of Levetiracetam Intravenous Infusion Relative to Oral Tablets and Multiple-Dose Pharmacokinetics and Tolerability of Levetiracetam Intravenous Infusion Compared with Placebo in Healthy Subjects Steven Ramael, MD1; Florence De Smedt, PhD2; Nathalie Toublanc, PharmD2; C h r i s t i a n Otoul, Eng2; Pierre Boulanger, PhD2;Jean-Michel Riethuisen, MD2; and Armel S t o c k i s , PhD2 15G5Life Sciences Services, Research Unit 5tuivenberg, Antwerp, Belgium; and 2UCB 5.A., Braine I'Alleud, Belgium

ABSTRACT Background: Antiopiloptic drugs aro usually administorod orally, but altornativo routos of drug dolivory may bo roquirod whon oral administration is not foasiblo. Objective: Tho purposo of this study was to ovaluato tho singlo-doso bioavailability of an IV formulation of lovotiracotam rolativo to oral tablots and tho multiplodoso tolorability and pharmacokinotics of this formulation comparod with placobo in hoalthy subjocts. Methods: This study consistod of 2 phasos. Subjocts ontorod tho first phaso, which was a singlo-doso, randomizod, opon-labol, 2-way crossovor bioavailability comparison of a 15-minuto IV infusion of lovotiracotam 1500 mg and throo 500-mg oral tablots. Subjocts thon ontorod tho socond phaso, a multiplo-doso, randomizod, doublo-blind, placobo-controllod (2:1), parallolgroup tolorability and pharmacokinotic study, in which thoy rocoivod 9 succossivo dosos of lovotiracotam 1500 mg IV or placobo at 12-hour intorvals. Plasma lovotiracotam concontrations woro dotorminod by gas chromatography with nitrogon-phosphorus dotoction. Tho comparison of bioavailability was basod on tho 90% CIs around tho goomotric moan ratios for AUC and C x (IV/oral). Results: Eightoon subjocts (9 mon, 9 womon) participatod in tho study. All subjocts woro whito. Thoir moan (SD) ago was 35.0 (9.3) yoars, moan woight 73.3 (14.2) kg, and moan body mass indox 23.9 (2.5) kg/m2. Aftor a singlo doso, tho IV infusion and oral tablot woro similar in torms of C ~ x (50.5 and 47.7 pg/mL, rospoctivoly) and AUC (392.4 and 427.9 pg • h/mL). Tho goomotric moan IV/oral ratios woro 92.2 (90% CI, 89.0-95.6) for AUC and 103.7 (90% CI, 91.6-117.4) 734

for C n ~ , indicating that the IV and oral formulations were biooquivalont. Aftor multiplo twico-daily infusions, stoady stato was roachod within 48 hours. Sovontoon (94%) of 18 subjocts had _>1 troatmontomorgont advorso ovont aftor singlo-doso administration. During tho singlo-doso phaso, tho incidonco of troatmont-omorgont advorso ovonts was 89% (16/18) for tho IV formulation and 72% (13/18) for tho oral tablots; during tho multiplo-doso phaso, tho incidonco of troatmont-omorgont advorso ovonts was 67% (8/12) in tho IV lovotiracotam group and 33% (2/6) in tho placobo group. Tho most common advorso ovonts in tho singlo-doso phaso were somnolonco (61% IV vs 28% oral) and postural dizzinoss (17% vs 39%, rospoctivoly). Tho most common advorso ovonts with IV lovotiracotam in tho multiplo-doso phaso were also somnolonco (33% vs 17% placobo) and postural dizzinoss (25% vs 0% placobo). Condusions: In thoso hoalthy subjocts, singlo dosos of lovotiracotam 1500 mg administorod as a 15-minuto IV infusion and as oral tablots were biooquivalont. Gonoral and local tolorability during multiplo dosing were good. Stoady stato was roachod within 48 hours. Dospito tho limitations of a study of short duration and small size conductod in hoalthy subjocts, tho findings suggost that uso of a 15-minuto IV infusion of lovotiracotam should bo furthor invostigatod. (CIin Ther. 2006;28:734-744) Copyright © 2006 Excorpta Modica, Inc.

AcceptedforpublicationMarch3, 2006. doi: ] 0.10] 6/j.clinthera.2006.05.004 0149 2918/06/$19.00 Printed in the USA.Reproductionin wholeor part is not permitted. Copyright© 2006 ExcerptaMedica, Inc. Volume 28 Number 5

S. Ramael et al.

Key words: levetiracetam, intravenous, pharmacokinetics, antiepileptic drugs, epilepsy.

INTRODUCTION

Antiepileptic drugs (AEDs) are usually administered orally, but alternative routes of drug delivery may be required in some patients or under certain treatment conditions. To date, IM, IV, and rectal formulations of AEDs have been approved for use in controlling seizures, whereas delivery by the nasal, buccal, and transdermal routes is under clinical investigation. 1 3 In some cases, use of an alternative route may improve efficacy and reduce toxicity. 1 For example, IV administration of AEDs is the route of choice when patients are temporarily unable to receive medications orally, including emergencies such as status epilepticus, when rapid drug delivery is required to control the acute episode without causing serious systemic or neurologic adverse effects. 4 The AED levetiracetam is used worldwide as an adjunctive treatment for partial-onset seizures in adults and children aged >4 years and is the first of the secondgeneration AEDs to be formulated for IV use. Levetiracetam has shown efficacy and tolerability in the treatment of refractory partial seizures in pivotal randomized, placebo-controlled studies ~7 and in a multicenter, open-label, community-based study designed to reflect typical clinical settings, s In the United States and many European countries, it is available as 250-, 500-, 750-, and 1000-mg tablets and as a 100-mg/mL solution for oral administration. The recommended clinical dosing range of levetiracetam for the adjunctive treatment of partial-onset seizures is 500 to 1500 mg BID.9 The present study was designed to evaluate the singledose bioavailability of levetiracetam 1500 mg delivered as a 15-minute IV infusion (100 mg/min) relative to the same dose given orally as three 500-mg oral tablets, and to compare the multiple-dose tolerability and pharmacokinetics of the levetiracetam 1500-mg IV infusion administered twice daily for 4.5 days with placebo.

SUBJECTS AND METHODS Study Population Healthy male and female subjects aged 18 to 55 years with a body mass index (BMI) of 19 to 28 kg/m2 were eligible for the study. The results of all physical and May2006

laboratory tests were to be within normal ranges at screening, but subjects with an abnormal finding could be enrolled at the investigator's discretion if the abnormality was considered clinically insignificant. All subjects provided written informed consent. Women were required to use a medically accepted method of contraception throughout the study. Pregnant or nursing women were ineligible. The study was conducted in accordance with Good Clinical Practice Guidelines, the principles of the Declaration of Helsinki, and all local laws and regulations. The protocol and informed consent form were approved by the ethics committee of the public hospitals of the city of Antwerp. The study was conducted at the SGS Biopharma Clinical Research Unit, Stuivenberg Hospital, Antwerp, Belgium.

Study Design This Phase I study consisted of 2 phases (Figure 1). The first phase was a single-dose, randomized, openlabel, 2-way crossover bioavailability study, with the 2 treatment periods separated by a 7-day washout. The second phase, which involved the same subjects, was a multiple-dose, randomized, double-blind, placebocontrolled, parallel-group tolerability and pharmacokinetic study lasting 4.5 days. During the single-dose phase, subjects were admitted to the study center in the evening before each treatment period. They were randomly assigned to receive levetiracetam 1500 mg administered IV or orally on the morning of day 1; after a 7-day washout, they received the alternative formulation. Subjects remained at the study center for at least 36 hours after administration of study drug. The multiple-dose phase began 2 days after administration of the second single dose. A 2-day interval was selected because blood sampling continued up to 36 hours after administration of the second single dose. On day 1 of the second treatment phase, subjects were randomly assigned in a 2:1 ratio to receive either levetiracetam or placebo administered as a 15-minute IV infusion every 12 hours for 4.5 days (from the morning of day i to the morning of day 5). Subjects remained at the study center until at least 24 hours after the last dose of study drug. On the days of single-dose administration and on the first and last days of the multiple-dose phase, the morning dose of study drug was administered after an overnight fast. 735

Clinical Therapeudc~

D o u b l e Blind M u l t i p l e Dose Phase

O p e n Label Single Dose Phase Period 1

._~ Screening Visit

Levetiracetam 1500 mg P©

Period 2

7 daywashout

Levetiracetam 1500 mg IV

2 days

._~

E 0

°E

Levetiracetam

7 daywashout Levetiracetam

1500 mg IV

1500 mg PO

2 days

Levetiracetam 1500 mg IV BID

45 days

Placebo IV BID

Figure 1. Study diagram. Each period of the single-dose phase involved serial blood sampling until 48 hours after dosing. The multiple-dose phase lasted 4.5 consecutive days and involved 9 successive IV infusions at 12-hourly intervals.

Study Drugs The oral dose consisted of three 500-mg levetiracetam tablets taken with 240 mL of water. The IV formulation consisted of sealed ampules containing levetiracetam 500 mg in 5 mL of sterile buffered saline, and the corresponding placebo ampules contained 5 mL of sterile buffered saline. For IV administration, the contents of 3 ampules were transferred by syringe into a 100-mL pouch of 0.9% sterile saline. The solution was infused over a 15-minute period through a venous catheter using a standard infusion pump.

Study Procedures and Tolerability Assessment Subjects were screened for eligibility within 3 weeks before administration of study drug. Tolerability assessments during the study included vital signs, laboratory parameters, and 12-lead electrocardiograms obtained before dosing, and at 5, 15, and 30 minutes, and 1 and 2 hours after dosing. Spontaneously reported adverse events were recorded throughout the study. Treatment-emergent adverse events were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) version 6.0. Their severity and relationship to study drug were evaluated by the study investigator. To assess the risk of pulmonary hypertension, Doppler echocardiography was performed at screening and before dosing and 7.5, 15, and 30 minutes 736

after dosing during the first and last IV infusions. The maximum velocity of tricuspid regurgitation jets (TRJ), time to peak flow velocity (AT), and blood flow were recorded. Arterial pulmonary hypertension was defined as an AT <100 milliseconds or a maximum TRJ velocity >3 milliseconds. 1° Blood samples for the determination of plasma concentrations of levetiracetam and its pharmacologically inactive carboxylic metabolite, ucb L057, were collected in lithium-heparin-containing tubes and centrifuged at 1600g for 10 minutes at 4°C. Serial samples were collected for up to 36 hours after a single dose; immediately before and 15 minutes after the start of the infusion during the multiple-dose phase (days 1-4); and for up to 12 hours after administration of the last IV infusion (day 5). Plasma samples were stored at -20°C until analyzed.

Analytical Methods Plasma concentrations of levetiracetam and ucb L057 were analyzed according to recommendations for bioanalytical method validation11 using methods described by Coupez et al. 12,13 Levetiracetam concentrations were determined by validated gas chromatography with nitrogen-phosphorus detection. 12,13 The quantification range was 0.5 to 40 l~g/mL. The overall recovery of levetiracetam quality-control samples analyzed during the study was 103.5%, 99.6%, and Volume 28 Number 5

S. Ramael et al.

100.0% at nominal concentrations of 1, 8, and 30 ~g/mL, respectively. Plasma concentrations of ucb L057 were measured by validated high-pressure liquid chromatography with electrospray ionization massspectrometric detection. 13 The quantification range was 0.02 to 2 ~g Eq levetiracetarrdmL. The overall recovery of ucb L057 quality-control samples analyzed during the study was 92.7%, 94.9%, and 89.7% at nominal concentrations of 0.06, 0.2, and 1.0 ~g Eq levetiracetam/mL, respectively. Pharmacokinetics

Pharmacokinetic parameters were calculated from the individual plasma concentration-time profiles using noncompartmental methods. The Cma~ and Tma~ were obtained directly from the measured plasma concentration-time curves. The AUC from time 0 to the last quantifiable concentration (AUC04) was computed using the linear trapezoidal rule. The AUC extrapolated to infinity was calculated as the sum of AUCc~t and Clast/)~z,where Clast is the last quantifiable concentration and Xz is the first-order terminal rate constant, obtained as the slope of the natural logarithm of plasma concentration-time data during the terminal phase. In the multiple-dose phase, the AUC for the interval (AUC~) of 12 hours after the last IV dose was calculated. The terminal elimination tl/2 was calculated as In 2/;~z. The accumulation ratio based on C n ~ (Rm~) was calculated as the ratio of the C ~ x at steady state to the C ~ after the first dose; similarly, the accumulation ratio based on A U C (Rauc) was calculated as the ratio of the A U C at steady state to the AUC after the first dose. The linearity factor was calculated as the ratio of the AUC, at steady state to the AUC after the first dose. 14 Total body clearance (apparent total body clearance for oral dosing) was calculated as dose/AUC, and Vd (apparent Vd for oral dosing) was calculated as CI/;~z. Both parameters were normalized by body weight. Pharmacokinetic parameters calculated for ucb L057 included C , Xz, tl/2, and AUC04. AUC was computed after single doses and AUC, after multiple doses. Calculations were performed using W i n N o n L i n version 4.01 (Pharsight Corporation, Mountain View, California).

Statistical Methods In the single-dose phase, the pharmacokinetics of levetiracetam after IV and oral dosing were compared May2006

using a univariate model of analysis of variance (ANOVA) adapted to the crossover design. The model included treatment, period, and sequence as fixed effects and subject nested to the sequence as a random effect, is The data were logarithmically transformed before statistical testing, and the bioequivalence of the 2 formulations was assessed for AUC, AUCc~t, and Cn~x using the standard 9 0 % CIs for the ratios of geometric means (AUCpo/AUCIv and C n ~ P O / C ~ x IV). 16 Bioequivalence was concluded if the 9 0 % CIs were contained within the equivalence range from 80% to 125%. 17 For all pharmacokinetic parameters, descriptive statistics were calculated from the individual pharmacokinetic parameters. In the multiple-dose phase, all pharmacokinetic parameters on day 7 were evaluated using descriptive statistics. In addition, after logarithmic transformation, the AUG t after the last IV dose on day 7 was compared with the AUC after the first IV dose (ie, IV treatment in the first phase) by A N O V A with treatment (single/multiple dosing) and subject as factors. The 9 0 % CI of the geometric mean ratio was computed. All statistical tests were 2-tailed, with significance set at P < 0.05. The intrasubject coefficient of variation from previous studies was 7.1% for AUC and 9.7% for Cn~x .12 Given the bioequivalence range from 80% to 125% and intrasubject variability of 9.7%, a sample size of 14 subjects (in a 2 × 2 crossover design) was required to yield at least 9 0 % power to conclude bioequivalence between the 2 formulations with a type I error of 0.05 and a true ratio of geometric means within the range from 90% to 111%. is Thus, 18 subjects were to be enrolled to ensure that at least 14 completed the first 2 study periods. Enrollment of this number and use of the previously described hypotheses would result in statistical power of 96%. Treatment-emergent adverse events were summarized descriptively by M e d D R A preferred term and treatment. Other safety parameters were evaluated descriptively. Doppler echocardiography parameters on the first and last days of the multiple-dose phase were summarized descriptively by treatment, and changes f r o m baseline were computed. N o other statistical analysis of the safety data was performed. Calculations were performed using SAS version 8.01 (SAS Inc., Cary, N o r t h Carolina) or StatXact version 4.02 (Cytel Software, Cambridge, Massachusetts).

737

Clinical Therapeudc~

RESULTS Study Population

Table I. Demographic characteristics o f study subjects. Values are mean (SD).

Eighteen subjects (9 men, 9 women) were enrolled, all of w h o m completed both phases of the study. All subjects were white and in good health. They ranged in age from 19 to 52 years (mean [SD], 35.0 [9.3] years), in weight from 50 to 94 kg (mean, 73.3 [14.2] kg), and in BMI from 19.7 to 27.3 kg/m 2 (mean, 23.9 [2.5] kg/m 2) (Table I). Mean (SD) systolic blood pressure was 120 (11) m m Hg and mean diastolic blood pressure was 76 (7) m m Hg; mean heart rate was 64 (11) beats/min and mean respiratory rate was 13 (4) breaths/ min. One subject received an incorrect dose of IV levetiracetam (-1200 mg) during the single-dose phase and was excluded from the pharmacokinetic evaluation for that part of the study only. During the multipledose phase, 12 subjects received levetiracetam and 6 received placebo.

M en (n 9)

Parameter

Worn en (n 9)

Total (N 18)

Age, y 35.4 (6.5) 34.6 (11.9) 35.0 (9.3) Weight, kg 84.0 (9.8) 62.6 (8.8) 73.3 (14.2) Height, cm 182.3 (4.8) 166.3 (7.3) 174.3 (10.2) BMI, kg/m 2 25.2 (2.2) 22.5 (2.0) 23.9 (2.5) BSA, m 2 BMI

2.1 (0.1)

1.7 (0.2)

1.9 (0.2)

body mass index; BSA body surface area.

(50.5 [18.8] pg/mL) was similar to that after oral dosing (47.7 [13.5] pg/mL) (Table II). The geometric mean ratio for Cn~x was 103.7 (90% CI, 91.6-117.4). After achievement of Cn~x, plasma levetiracetam concentrations declined monoexponentially over time, with a mean tin of 7.16 (1.13) and 7.22 (1.16) hours for the respective formulations. Also similar after IV and oral administration were the AUC 0 t (378.6 [73.2] and 414.7 [88.6] lag. h/mL) and AUC (392.4 [71.2] and 427.9 [89.6] lag. IdmL). The 90% CIs around the geo-

Single-Dose Pharmacokinetics The mean levetiracetam plasma concentrationtime profiles after a single 1500-mg dose administered either as a 15-minute IV infusion or orally are shown in Figure 2. The mean (SD) C after the IV infusion

IV Infusion Oral tablet 60

60

50 4O

50 <2 E E ~-G

30 40

2O 10

30

0 0

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

20

Time (h)

~u 10 0

0

6

ll2

ll8

214

310

I 36

Time (tl) Figure 2. Mean (SD) plasma concentrations of levetiracetam overtime after administration of a single IV (1500 mg) or oral (three 500-mg tablets) dose (n = 17). The inset shows the interval from 0 to 4 hours. Limit of quantification, 0.5 pg/mL.

738

Volume 28 Number 5

S. Ramael et aJ.

Table II. Pharmacokinetic parameters after administration of single 1800-mg IV and oral doses of levetiracetam

in 17 healthy subjects. Values are arithmetic mean (SD), unless o t h e ~ i s e specified.

Param eter

Geometric Mean Ratio, IV/Oral (90% CI)

IV Levetiracetam

Oral Levetiracetam

%CV

AUC0 t, Pg" h/mL

378.6 (73.2)

414.7 (88.6)

6.4

91.7 (88.3 95.3)

AUC, pg. h/mL

392.4 (7].2)

427.9 (89.6)

5.9

92.2 (89.0 95.6)

AUC,, pg. h/mL

267.0 (58.7) 47.7 (13.5)

20.8

103.7 (91.6 117.4)

Crr~, pg/mL

80.8 (18.8)

C15,, pg/mL

47.8 (20.2)

T~ra×, h Median Range

0.25 0.22 2.0

0.75 0.S 2.0

tl/2, h

7.16 (1.13)

7.22 (1.16)

CI or CI/F, mL/min/kg

0.92 (0.17)

0.85 (0.15)

Vd or Vd/F, L/kg

0.86 (0.09)

0.82 (0.07)

CV

intrasubject coefficient of variation; AUC0<

AUC fiom time 0 to the last quantifiable concentration; A U C

AUC over

the 12 hour interval after the last IV dose; Cls, plasma concentration at the end of the 15 minute infusion; CI total body clearance (apparent CI [CI/F] used for oral dosing); Vd volume of distribution (apparent Vd [Vd/F] used for oral dosing).

metric mean ratios for AUC04 and AUC were contained within the range for bioequivalence (geometric mean ratio [90% CI], 91.7 [88.3-95.3] and 92.2 [89.0-95.6], respectively). Intrasubject variability (ANOVA) was low for AUC (5.9%) and moderate for C ~ (20.8%). An a posteriori power analysis using this variability and the observed ratios provided >99% power to detect bioequivalence in 18 subjects for AUC and 79% power for C . The pharmacokinetics of the levetiracetam metabolite ucb L057 were similar after administration of a single IV or oral dose of levetiracetam. The mean (SD) Cmax after IV and oral dosing was 0.95 (0.19) and 1.02 (0.18) llg Eq levetiracetardmL, respectively (geometric mean ratio, 92.6; 90% CI, 87.4-98.1). The median Tma~ was 6 hours (range, 3-9 hours) after IV administration and 6 hours (range, 6-12 hours) after oral administration. The mean tl/2 was 8.4 (1.1) and 8.5 (1.1) hours after IV and oral dosing. Exposure to ucb L057 also was similar with IV and oral administration: the mean AUCc~ t was 17.2 (4.3) and 18.8 (4.4) llg Eq levetiracetam, h/mL (geometric mean ratio, 90.8; 90% CI, 86.3-95.5). The corresponding AUC values were 18.3 (5.3) and 19.1 (4.3) llg Eq levetiracetardmL (geometric mean ratio, 92.8; 90% CI, 87.4-98.6).

May2006

Multiple-Dose Pharmacokinetics Figure 3 illustrates the mean plasma levetiracetam concentrations immediately before and at the end of each 15-minute infusion, as well as the complete concentration-time profile obtained after the last dose. Steady state was achieved 48 hours after the initiation of multiple IV dosing, as confirmed by the slope of the trough values from 48 to 108 hours (linear regression of trough values vs time), which was not statistically different from zero. As expected, the mean (SD) Cn~x after multiple doses of IV levetiracetam given twice daily (71.7 [21.3] IJg/mL) was higher than that after a single IV dose during the single-dose phase (52.4 [22.3] IJg/mL) (Table III). The mean C ~ n during administration of IV levetiracetam twice daily was 14.1 (3.75) IJg/mL. Single and multiple doses of IV levetiracetam were similar in terms of AUC or AUC~ (389.4 [77.6] and 371.9 [80.9] lag • h/mL, respectively). The geometric mean ratio of the AUC~ at day 7 to the AUC at day 1 was 95.2 (90% CI, 89.6-101.2). The mean (SD) R ~ x was 1.51 (0.48), and the mean RAuC was 1.43 (0.23); these values were similar to those predicted from the formula 1/(1-exp[-X z . ~]) under the assumption of monocompartmental and linear pharma-

739

Clinical Therapeutics

100

<2 E E

ed

80

60

T

40

i ".,.

20 0

l

: '"k~

112

:',,

,,

'.

""", i

,,

214

""'',, jJ

....,

316

418

610

712

814

916

108

Time (h) Figure 3. Mean (SD) predose and 1S-minute postdose plasma concentrations of levetiracetam after 8 successive IV infusions of 1500 mg at 12-hourly intervals and the full concentration-time profile after the ninth dose (n = 12). Limit of quantification, O.S p g / m L cokinetics. Pharmacokinetic linearity was further evidenced by the mean linearity factor of 0.96 (0.11). The mean (SD) Cn~x and Cn~n of ucb L057 during administration of levetiracetam 1500 mg IV twice daily were 1.66 (0.45) and 0.89 (0.34) lag Eq levetiracetam/ mL, respectively. Tm~ occurred at a median of 3 hours after administration of levetiracetam, and the C ~ n of ucb L057 remained fairly stable after the first day of dosing. Tolerability Seventeen (94%) of 18 subjects had _>1 treatmentemergent adverse event after single-dose administration. The incidence of treatment-emergent adverse events was 89% (16/18) for the IV formulation and 72% (13/18) for oral administration. After the administration of multiple IV doses, the proportion of subjects with treatment-emergent adverse events was 67% (8/12) in the levetiracetam group and 33% (2/6) in the placebo group. The most common treatment-related adverse events after single-dose administration were somnolence and postural dizziness, reported in a respective 61% and 17% of subjects after IV administration and 28% and 39% of subjects after oral administration (Table IV). 740

Two subjects (11%) experienced short-lasting pruritus at the injection site after IV infusion in the single-dose phase, but this symptom was not reported during the multiple-dose phase. The most common treatmentrelated adverse events with IV levetiracetam during the multiple-dose phase also were somnolence (33 %) and postural dizziness (25%); the most common adverse events with placebo were somnolence, dizziness, and euphoric mood (17% each). All adverse events were considered by the investigator to be mild in intensity, with the exception of i case of moderate influenza-like illness occurring after singledose administration. This illness was judged unrelated to study drug. There were no serious adverse events, and none of the subjects discontinued treatment. No clinically relevant changes or abnormalities in laboratory values were observed during the study. Intermittent asymptomatic decreases in systolic blood pressure (to <100 m m Hg) were noted in 2 subjects during multiple dosing of IV levetiracetam; however, this pattern was observed before as well as after dosing, and systolic blood pressure remained low but within the normal range in both patients from screening to discharge. No other relevant changes in vital signs or electrocardiographic parameters, including Volume 28 Number 5

S. Ramael et aJ.

Table III. Pharmacokinetic parameters after IV infusion o f single and multiple 1500-mg doses of levetiracetam in 12 healthy subjects. Values are arithmetic mean (SD), unless otherwise specified.

ParameEer

Single Dose

MulEiple Doses (9Eh Infusion)

AUC or AUCp yg. h/mL

389.4 (77.6)

371.9 (80.9)

Cm~, yg/mL

52.4 (22.3)

71.7 (21.3)

Tmax, h Median Range

0.25 0.22 2.0

0.25 0.20 0.27

Cmin~ yg/mL

14.1 (3.75)

Rm~

1.51 (0.48)

RAUc

1.43 (0.23)

LF

0.96 (0.11 )

AUC AUCowrthe12 hourintervalafterthelastlVdose; Rma× accumulation ratio calculated from the Cm~ at steady state and after the first dose; RAUc accumulation ratio calculated from the AUCr at steady state and after the first dose; LF linearity factor (ratio of AUC at steady state to AUC after the first dose).

the QT interval, were observed during either part of the study. There were no relevant changes from baseline in any Doppler echocardiographic parameter during multiple dosing, and all echocardiographic parameters recorded were within normal physiologic ranges. Values for cardiac output were constant during Doppler examination. DISCUSSION Although AEDs are generally administered orally, some patients may be unable to swallow an oral medication and/or have a temporary need for IV medication (eg, in medical or surgical settings in which oral medications may not be appropriate). In such cases, the availability of alternative methods of drug delivery adds flexibility. Among the older AEDs, valproate, phenobarbital, phenytoin, fosphenytoin, and carbamazepine have been formulated for IV administration. Levetiracetam is highly water soluble (1 g/mL) and is characterized by low plasma protein binding (<10%), linear pharmacokinetics after oral administration, a major biotransformation pathway not dependent on May 2006

the cytochrome P450 system, and low potential for clinically significant pharmacokinetic drug-drug interactions. 9,19,2° In patients with partial-onset seizures, adjunctive therapy with levetiracetam is well tolerated, with an incidence of adverse events unrelated to dose within the recommended dosing range from 1000 to 3000 mg/d.21 Based on the favorable pharmacokinetic, efficacy, and tolerability profiles of levetiracetam, an injectable formulation was developed for IV infusion. The purpose of this study was to assess the relative bioavailability, pharmacokinetics, and tolerability of IV levetiracetam in healthy subjects. Based on the 90% CIs of the geometric mean ratios for AUC0~, AUC, and Cn~x, which were within the range from 80% to 125%, a single 1500-rag dose of levetiracetam administered as a 15-minute IV infusion was bioequivalent to the same dose given as oral tablets. The levetiracetam plasma concentration-time curves after single IV and oral doses were essentially superimposable for time points after the attainment of oral Cm~. The bioequivalence of the IV and tablet formulations was expected given the rapid and almost complete oral absorption of levetiracetam.22,23 Based on the 90% CI of the geometric mean ratio of the AUCt after the last dose to the AUC after single doses, which was within the range from 80% to 125%, the pharmacokinetics of IV levetiracetam were judged to be time independent during 9 successive 12-hourly infusions. The linearity factor, calculated from the ratio of the AUCt at steady state to the AUC after the first dose, was 0.96, and the RAUC of 1.43 was consistent with the value expected for linearity. As has been observed with the oral route, 22 steady state was achieved within 48 hours after the initiation of the IV infusion. Intravenously administered levetiracetam was well tolerated. Consistent with the reported safety profile of oral levetiracetam,21,24 the most common adverse events with IV levetiracetam in this study were somnolence and postural dizziness. Somnolence was the most common adverse event after a single IV dose (16% IV vs 28% oral), whereas postural dizziness was the most common adverse event after a single oral dose (39% oral vs 17% IV). During multiple dosing of IV levetiracetam, the incidence of somnolence and dizziness was higher with levetiracetam than with placebo (somnolence: 33 % vs 17%, respectively; postural dizziness: 25% vs 0%). The relevance of these observations beyond the context of a well-controlled 741

Clinical Therapeudc~

Table IV. Summary of treatment-emergent adverse events (no. [%] of subjects). Unless otherwise indicated, all events were judged by the investigator to have a possible, probable, or highly probable relationship to study drug. Single Dose

MedDRA System/ Preferred Term

IV Levetiracetam (n 18)

Multiple Doses

Oral Levetiracetam (n 18)

IV Levetiracetam (n 12)

IV Placebo (n 6)

Nervous system disorders Dizziness, postural Dizziness Somnolence Headache Disturbance in attention General disorders and administration site conditions Injection site pruritus Fatigue

Thirst Feeling cold Influenza like illness Chest pain Infections and infestations Nasophawngitis Musculoskeletal and connective tissue Chest wall pain

3 I 11 3

(I 7) (6) (61) (17)* 0

7 3 8 I

(39) (17) (28) (6)

2 (1 1 ) 1 (6)

3 i 4 3 i

(28) (8) (33) (28)t (8)

0 i (17) i (17)

0 0

0 1 (6)* 1 (6)* 0

I (8) 0 0 0

0

I (6)*

I (17)*

0

0

1 (6)*

0

0

Investigad ons Blood pressure decrease

0

2 (17)

0

Psychiatric disorders Euphoric mood

0

I (8)

I (17)

I (8)

0

1 (8)* 1 (8)* 1 (8)

0 0 0

Gastrointestinal disorders Dry mouth Flatulence Loose stools Nausea

0 1 (6)* 2 (11 )* 0

MedDRA Medical Dictionary for Regulatory Activities. *Two of these adverse eventswere not considered related to study drug. TOne of these adverse eventswas not considered related to study drug. ~No[ considered related [o study drug.

Phase I study in healthy young subjects is difficult to determine. The safety profile of the levetiracetam infusion will have to be assessed prospectively as well as retrospectively in clinical practice in adequate numbers of patients with epilepsy. Furthermore, the study findings regarding the tolerability of the levetiracetam infusion cannot be extended to special groups, such as pediatric or elderly patients, without specific evalu742

ation in those populations. In addition, observations in healthy subjects cannot be extrapolated to the use of higher doses or infusion rates. No clinically significant changes in laboratory values were observed in this study, which is consistent with clinical experience with the oral tablet. 24 The results of Doppler echocardiography performed during the multiple-dose phase suggested no changes in pulVolume 28 Number 5

S. Ramael et al.

monary hemodynamics after infusion of IV levetiracetam. Subjects who received IV levetiracetam had few adverse local reactions (11% during the single-dose phase, 0% during the multiple-dose phase). CONCLUSIONS A single 1500-mg dose of levetiracetam administered as a 15-minute IV infusion was bioequivalent to the same dose given as oral tablets in these healthy volunteers. General and local tolerability were good during multiple twice-daily dosing, and steady state was reached within 48 hours. Despite the inherent limitations of a study of short duration conducted in a small group of healthy subjects, the findings suggest that the 15-minute infusion of IV levetiracetam should be further investigated.

ACKNOWLEDGMENTS This study was sponsored by UCB S.A., Braine l'Alleud, Belgium. The authors thank Prof. Jean-Luc Vachiery, Erasme Hospital, Free University of Brussels, Belgium, for performing the echocardiographic examinations. REFERENCES 1. Fisher RS, HoJ. Potential new methods for antiepileptic drug delivery. CNS Drugx. 2002;16:579 593. 2. CereghinoJJ, Mitchell WG, MurphyJ, et al, for the North American Diastat Study Group. Treating repetitive seizures with a rectal diazepam formulation: A random ized study. Neurology. 1998;51:1274 1282. 3. FisginT, Gurer Y, Tezic T, et ah Effects of intranasal mid azolam and rectal diazepam on acute convulsions in chil dren: Prospective randomized study.j Child Neurol. 2002; 17:123 126. 4. SirvenJl, Waterhouse E. Management of status epilepti cus. Am ,CamPhysician. 2003;68:469 476. 5. Ben Menachem E, Falter U, for the European Levetirace tam Study Group. Efficacy and tolerability o f levetirace tam 3000 mg/d in patients with refiactory partial seizures: A multicenter, double blind, responde~selected study evaluating monotherapy. Epilepsia. 2000;41:1276 1283. 6. CereghinoJJ, Biton V, Abou Khalil B, et ah Levetiracetam for partial seizures: Results o f a double blind, randomized clinical trial. Neurolo~. 2000;55:236 242. 7. Shorvon SD, Lowenthal A, Janz D, et al, for the Eu ropean Levetiracetam Study Group. Multicenter double blind, randomized, placebo controlled trial o f levetiracetam as add on therapy in patients with refiactory partial seizures. Epilepsia. 2000;41:1179 1186.

May2006

8. Morrell MJ, Leppik I, French J, et ah The KEEPER trial: Levetiracetam adjunctive treatment o f partial onset seizures in an open label community based study [pub lished correction appears in Epilepsy Res. 2003:56:209 210]. EpilepsyRes. 2003;54:153 161. 9. Patsalos PN. Clinical pharmacokinetics o f levetiracetam. Clin Pharmacokinet. 2004;43:707 724. 10. Naeije R, Torbicki A. More on the noninvasive diagnosis o f pulmonary hypertension: Doppler echocmdiography revisited. Eur Respirj. 1995;8:1445 1449. Editorial. 11. Shah VP, Midha KK, Findlay JW, et ah Bioanalytical method validation a revisit with a decade o f progress. Pharm Res. 2000;17:1551 1557. 12. Coupez R, Straetemans R, Sehgal G, et ah Levetiracetam: Relative bioavailability and bioequivalence o f a 10% oral solution (750 mg) and 750 mg tablets, j Clin Pharmacol. 2003;43:1370 1376. 13. Coupez R, NicolasJM, Browne TR. Levetiracetam, a new antiepileptic agent: Lack o f in vitro and in vivo pharmaco kinetic interaction with valproic acid. Epilepsia. 2003;44: 171 178. 14. Cawello W, ed. Pamrnete~ for Compartmen~Free Phar macokinetics. Standa~zlisation of Study Desie~, Data Analysis and Reporting. Aachen, Germany: Shaker Verlag; 1999. 15. Jones B, Kenward MG. Desi~ andAnalfiis 0fO0ss over Trials.

London, UK: Chapman and Hall; 1989. 16. Steinijans VW, Hauschke D. Update on the statistical analysis of bioequivalence studies. Intj Gin Pharmacol Ther Toxicol. 1990;28:105 110. 17. Chow SC, Liu JP. Desi~ and Analysis of Bioavailability and Bioequivalence Studies. 2nd ed. New York, NY: Marcel Dekker; 1998. 18. Diletti E, Hauschke D, Steinijans VW. Sample size determi nation for bioequivalence assessment by means of confi dence intervals. Intj Clin Pharmacol Ther Toxicol. 1991;29: 1 8. 19. Perucca E, Gidal BE, Baltes E. Effects of antiepileptic comedication on levetiracetam pharmacokinetics: A pooled analysis of data from randomized adjunctive the~ apy trials. EpilepsyRes. 2003;53:47 56. 20. Gidal BE, Baltes E, Otoul C, Perucca E. Effect of leveti racetam on the pharmacokinetics of adjunctiveantiepileptic drugs: A pooled analysis of data from randomized clinical trials. EpilepsyRes. 2005;64:1 11. 21. Harden C. Safety profile o f levetiracetam. Epilepsia. 2001; 42(Suppl 4):36 39. 22. Patsalos PN. Pharmacokinetic profile o f levetiracetam: Towmd ideal characteristics. Pharmacol Ther. 2000;85: 77 85. 23. Strolin Benedetti M, Whomsley R, Nicolas JM, et ah Pharmacokinetics and metabolism o f 14C levetiracetam, a new antiepileptic agent, in healthy volunteers. Eurj Clin Pharmacol. 2003;59:621 630.

743

Clinical Therapeudc~

4. French J, Edrich P, CramerJA. Asys tematic review of the safety profile of levetiracetam: A new antiepileptic drug. EpilepsyRes. 2001;47:77 90.

Address correspondence to: Steven Ramael, MD, SGS Life Sciences Services, Research Unit Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerp, Belgium. E-mail: [email protected] 744

Volume 28 Number 5