Clin Drug Investig DOI 10.1007/s40261-015-0303-9
ORIGINAL RESEARCH ARTICLE
Pharmacokinetics, Safety and Bioequivalence of Levetiracetam Intravenous Infusion and Oral Tablets in Healthy Chinese Subjects Nathalie Toublanc1 • Xinlu Du2 • Yun Liu3 • Qian Chen3 • Pritibha Singh4,6 Robert Chan5,7 • Armel Stockis1
•
Ó Springer International Publishing Switzerland 2015
Abstract Background and Objective Levetiracetam is available in China as adjunctive oral therapy for partial-onset seizures. This study was conducted to evaluate the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg (Part A), and to assess the pharmacokinetics of multiple-dose intravenous infusion at the same dose (Part B) in healthy Chinese subjects. Methods Part A was an open-label, crossover comparison (intravenous vs. oral), while Part B was a double-blind, parallel-group study of intravenous levetiracetam versus intravenous placebo administered for 5 days. Results Bioequivalence was demonstrated between the 45-min intravenous infusion and oral tablets, with geometric mean area under the plasma concentration–time curve (AUC) from time 0 to infinity (AUC?) 492.3 and 506.8 lgh/mL, and geometric mean maximum concentration (Cmax) 65.12 and 55.93 lg/mL for intravenous infusion and oral dosing, respectively. Linear pharmacokinetics were demonstrated (geometric least-squares mean AUC during the dosing interval s at steady state (AUCs,ss) 475.6 lgh/mL; geometric & Nathalie Toublanc [email protected] 1
UCB Pharma, Chemin du Foriest, 1420 Braine-l’Alleud, Belgium
2
UCB Pharma, Shanghai, China
3
Shanghai Xuhui Central Hospital, Shanghai, China
4
UCB Pharma, Monheim, Germany
5
UCB Pharma, Tokyo, Japan
6
Present Address: Hexal AG, Sandoz Biopharmaceuticals, Hlozkirchen, Germany
7
Present Address: Biogen Idec Japan Ltd, Tokyo, Japan
least-squares mean AUC? after single dose 501.7 lgh/mL; linearity factor = 0.948). Geometric mean Cmax (77.44 lg/ mL) and AUCs,ss (475.6 lgh/mL) of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the terminal half-life of levetiracetam after a single dose (7.13 h). A theoretical accumulation of approximately 40 % would be expected after multiple doses, which is consistent with the calculated accumulation of 18.0 and 43.5 % (Rmax and RAUC, respectively). Conclusions Intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects and is a suitable alternative for levetiracetam administration in patients who are temporarily unable to take their medication orally. Key Points Although levetiracetam is usually administered orally, intravenous administration provides an important alternative for patients who are temporarily unable to take oral medication. This study evaluated the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg, and assessed the pharmacokinetics of multiple-dose intravenous infusion at the same dose in healthy Chinese subjects. Results from this study were consistent with historical data in other ethnic groups and demonstrated that intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects.
N. Toublanc et al.
1 Introduction Levetiracetam [KeppraÒ; (-)-(S)-a-ethyl-2-oxo-1-pyrrolidine acetamide], an antiepileptic drug (AED), is available in China as adjunctive oral therapy for adults and children (from 1 month of age) with partial-onset seizures. Levetiracetam is rapidly absorbed, with peak plasma concentrations within 0.5–2.3 h after dosing, and has linear pharmacokinetics [1–3]. Although levetiracetam is usually administered orally, intravenous administration provides an important alternative for patients who are temporarily unable to take oral medication due to medical conditions associated with swallowing problems, upper gastrointestinal intolerance or malabsorption (e.g. altered state of consciousness, acute upper gastrointestinal dysfunction, or having to comply with a nil-by-mouth regimen preoperatively or postoperatively). Intravenous administration enables the patient to continue levetiracetam treatment and minimises the risk of destabilising seizure control when oral administration is temporarily infeasible. This study was conducted to evaluate the bioequivalence of intravenous levetiracetam and oral levetiracetam (Part A), and to assess the pharmacokinetics of multiple-dose intravenous levetiracetam (Part B) in healthy Chinese subjects. The safety of intravenous levetiracetam was assessed in both parts and compared with placebo over a 5-day treatment period in Part B. The study was performed to support a submission for the intravenous formulation of levetiracetam in China, as requested by the China Food and Drug Administration (CFDA). The dose selected for this study reflected the maximum recommended dose per intake/administration based on current labelling (1500 mg twice daily, i.e. 3000 mg/day). The dose of 1500 mg has also been used in previous bioequivalence studies [3–6]. A crossover design was chosen for the bioequivalence part of the study (Part A) since it allowed within-subject comparisons of the two levetiracetam formulations. A treatment duration of 5 days was chosen for the multiple-dose part of the study (Part B) because steady state is reached within 2 days with levetiracetam and because most intravenous AED courses are relatively short in duration.
2 Methods This clinical study was conducted between May and July 2012 in the Clinical Research Unit of Shanghai Xuhui Central Hospital, China. The study consisted of two parts. Part A [NCT01618903] was an open-label, crossover comparison of intravenous infusion versus oral 1500 mg
levetiracetam, while Part B [NCT01618877] was a doubleblind, parallel-group comparison of multiple-dose intravenous infusion levetiracetam versus placebo. This research followed the ethical principles for medical research set forth in the Declaration of Helsinki 1964, as modified by subsequent revisions. Approval for the study was obtained from an Independent Review Board and informed consent was obtained in writing from all participants prior to initiating any study-related medical procedure. 2.1 Study Population The study population consisted of 24 healthy subjects (12 males and 12 females). To be included in the study, subjects had to be aged 18–40 years and of Chinese descent, with all four grandparents born in China. All participants had to be considered in good health, with a bodyweight C50 kg and body mass index (BMI) between 19 and 24 kg/ m2. They were stratified by sex and randomised to one of two treatment sequences in Part A (12 received intravenous levetiracetam followed by oral levetiracetam, and 12 received oral levetiracetam followed by intravenous levetiracetam). In Part B, subjects were randomised to intravenous levetiracetam (n = 18) or intravenous placebo (n = 6). 2.2 Study Design 2.2.1 Bioequivalence Study Design—Part A Part A was open-label. All participants received a single dose of each treatment, with a 7-day washout between treatments to exclude any carryover effects. The treatments were (1) levetiracetam 1500 mg (500 mg/5 mL vials) administered as a 45-min intravenous infusion diluted in 100 mL 0.9 % saline solution, and (2) levetiracetam 3 9 500 mg tablets. The oral dose was taken with 200 mL of water. The intravenous formulation consisted of sealed vials containing approximately 5.4 mL of levetiracetam 100 mg/mL solution of sterile buffered saline. For intravenous administration, a total 15.0 mL of levetiracetam intravenous solution from three vials was transferred by syringe into a 100 mL pouch of 0.9 % sterile saline. The solution was infused over a 45-min period through a venous catheter. Infusion time was standardised at 45 min, irrespective of whether the whole dose had been administered; this was done in order to accurately determine maximum plasma concentration (Cmax). Blood samples were taken for pharmacokinetic analysis at the following timepoints: predose and at 15, 30, and 45 min, and 1, 1.5, 2, 3, 6, 9, 12, 24, and 36 h after oral
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects
dose administration or after the start of the intravenous infusion. 2.2.2 Multiple-Dose Pharmacokinetic Study Design—Part B Subjects who completed Part A were randomised to one of two 45-min intravenous infusion treatments in Part B: levetiracetam 1500 mg (500 mg/5 mL vials) diluted in 100 mL 0.9 % saline solution or placebo (15 mL 0.9 % saline solution) added to 100 mL 0.9 % saline solution. Part B treatment began 48 h after completion of the last treatment in Part A. Part B infusions were administered every 12 h for 4.5 days (a total of nine infusions). Only the pharmacist dispensing the prescription was unblinded; as such he did not participate in any other study activities. Measures were taken to ensure that levetiracetam and placebo were indistinguishable in appearance; a total 15.0 mL of levetiracetam or placebo solution from three vials was transferred by syringe into a 100 mL pouch of 0.9 % sterile saline for infusion. For each of the first eight infusions in Part B, blood samples were taken for pharmacokinetic analysis predose and at 45 min, i.e. at the end of the infusion (a total of 16 plasma samples). For the last infusion, blood samples were obtained at predose and at 15, 30, and 45 min, and 1, 1.5, 2, 3, 6, 9, 12, 24, and 36 h after the start of the infusion (13 samples). 2.3 Safety Safety was evaluated throughout the study by monitoring adverse events (AEs), laboratory parameters, and vital signs, and by conducting electrocardiograms and physical examinations. 2.4 Analytical Determinations Plasma levetiracetam determinations were performed by Frontage Laboratories (Shanghai) Co., Ltd, Shanghai, China. The assay method was based on liquid chromatography with triple-stage quadrupole mass spectrometric detection (LC/MS/MS) and used a Sciex API4000 instrument with Turbo Ion Spray interface (AB Sciex, Framingham, MA, USA). Levetiracetam-D6 was used as the internal standard. Levetiracetam and internal standard were extracted from plasma by solid-phase extraction using Waters Sep-PakÒ (C18 100 mg) 96-well plates (Waters Corporation, Milford, MA, USA). Reversed-phase highperformance liquid chromatography separation was achieved using a Waters SunfireTM C18 column (50 mm 9 2.1 mm internal diameter, 3.5 lm particle size) protected by a 10-mm guard column. The mobile phase was a gradient of water and acetonitrile containing 0.1 %
trifluoroacetic acid adjusted at pH 2.5. Detection was set at mass transitions of 170.9 ? 125.9 m/z for levetiracetam and 177.0 ? 132.0 m/z for levetiracetam-D6 in total ion scan, positive mode. The method was validated in human plasma in the concentration range from 0.1 to 100.00 lg/mL. The intrarun precision and accuracy of the analytical method were evaluated after replicate analysis (n = 6 at each concentration level) of validation samples prepared in human Liheparinized plasma at five concentration levels: lower limit of quantification (0.1 lg/mL), low concentration (0.3 lg/ mL), mid-range concentration (25.0 lg/mL), high concentration (80.0 lg/mL) and upper limit of quantification (100.0 lg/mL). Three intra-run determinations were performed over three different runs. An independent calibration curve was freshly prepared for each run. Intermediate precision, expressed as a coefficient of variation, was 10.7, 5.9, 2.4, 2.1, and 3.7 %, respectively; recovery, expressed as a percentage of nominal concentration, was 103.0, 107.7, 107.4, 100.4, and 100.9 %, respectively. 2.5 Pharmacokinetic and Statistical Analysis The pharmacokinetic and statistical calculations were performed using Phoenix WinNonlin version 6.2 (Certara Inc., St. Louis, MO, USA) and SAS version 9.1.3 (SAS Institute Inc., Cary, NC, USA), respectively. Pharmacokinetic parameters were derived by noncompartmental analysis, using actual sampling times. Parameters calculated for levetiracetam in Part A included Cmax, time to Cmax (tmax), plasma concentration at the end of the 45-min infusion (C45,IV), area under the plasma concentration-versus-time curve from time zero to the last quantifiable concentration (AUCt), AUC over the dosing interval (s) 0–12 h (AUCs,Day1), AUC from time zero to infinity (AUC?), terminal half-life (t), total body clearance (CLIV) and volume of distribution (Vz,IV) after intravenous infusion, as well as apparent total body clearance (CL/F) and volume of distribution (Vz/F) after oral administration. Parameters calculated for levetiracetam in Part B included Cmax, AUC during the dosing interval s after the last intravenous dose at steady state (AUCs,ss), minimum plasma concentration after intravenous infusion (Cmin) and t. Study staff were instructed to adhere to the 45-min intravenous infusion time even if the entire volume of levetiracetam had not been administered at the end of 45 min; therefore, analysis was conducted on dose-normalised and nondose-normalised parameters. For the primary pharmacokinetic parameters (AUC?, AUCt, and Cmax), the point estimates and the 90 % confidence intervals (CIs) of the geometric mean ratio between the intravenous and oral tablet formulations were computed. The calculations were made using the least-squares
N. Toublanc et al.
means and the root mean square of error from an analysis of variance (ANOVA) of the log-transformed (natural) data with subsequent exponential transformation (i.e. back transformation). Intrasubject variability was also estimated from the ANOVA. The ANOVA model included factors of treatment, period, and sequence as fixed effects, and subject nested within sequence as the random effect. Bioequivalence was to be concluded if the 90 % CIs for the intravenous/oral ratio were fully included in the acceptance range for bioequivalence of 0.8–1.25 for AUC? and AUCt, and 0.7–1.43 for Cmax. Single- and multiple-dose pharmacokinetics were compared by calculating the linearity factor and the accumulation ratios of AUC (RAUC) and Cmax (Rmax). The linearity factor was calculated as the ratio of AUCs,ss and AUC? after single-dose administration. The point estimates and 90 % CIs of the geometric mean ratio between single dose and multiple doses were computed using the least squares means and the root mean square of error from an ANOVA of the log-transformed (natural) data with subsequent exponential transformation (i.e. back transformation). Intrasubject variability was also estimated from the ANOVA. The ANOVA model included factors of treatment (single or multiple doses) and subject as fixed effects. Similarly, the AUCs,ss in Part B versus AUCs,Day1 after single-dose administration in Part A were used to calculate the RAUC. The Rmax was assessed by comparing Cmax at steady state (Cmax,ss) with Cmax,Day1 after single-dose administration. For sample size estimation, the intrasubject coefficient of variation was assumed to be 3.6 % for AUCt and 22.8 % for Cmax. Based on a true value of 1.14 for the Cmax ratio, 20 subjects were required to achieve 90 % power for the assessment of bioequivalence at a significance level of a = 0.05. A sample size of 24 subjects was chosen, to take into account possible dropouts.
3 Results 3.1 Study Population The 24 subjects (12 males, 12 females) had a mean age of 24.8 years (range 19–31 years), mean height of 164.1 cm (range 153–172 cm), mean bodyweight of 58.76 kg (range 50.3–69.5 kg), and mean BMI of 21.79 kg/m2 (range 19.1–24.0 kg/m2). With regard to sex, no differences were noted for age and BMI between male and female subjects; mean height and weight were higher in male subjects compared with female subjects. Given stratification by sex, the groups in both Parts A and B were well balanced, with no notable differences in demographics between the groups.
3.2 Study Drug Exposure The actual intravenous dose in Part A and the final intravenous dose in Part B differed from the protocol dose (1500 mg) by more than 10 % for three subjects. Intravenous pharmacokinetic parameters were therefore dosenormalised. As results from analyses conducted on dosenormalised and nondose-normalised parameters were similar, only dose-normalised parameters were presented. 3.3 Comparison of Single-Dose Intravenous and Oral Levetiracetam Overall, levetiracetam geometric mean dose-normalised plasma concentration-versus-time profiles for oral and intravenous infusion were similar (Fig. 1). During the first 45 min, geometric mean plasma concentration increased faster for intravenous infusion, reaching a higher mean concentration at 45 min (approximately 65 lg/mL) than for oral dosing at the same timepoint (approximately 40 lg/mL). Spaghetti plots for single intravenous and oral doses are provided in Figs. 2 and 3, respectively. Geometric mean AUC? was similar between intravenous infusion (492.3 lgh/mL) and oral tablet dosing (506.8 lgh/mL) (Table 1). Geometric mean Cmax after intravenous infusion (65.12 lg/mL) was 16 % higher than after oral tablet administration (55.93 lg/mL). The range of Cmax values for intravenous infusion was within the range for oral administration. Since study staff were instructed to stop the intravenous infusion at 0.75 h (45 min), irrespective of whether the whole dose had been given, median tmax for the intravenous infusion was 0.73 h (range 0.70–0.77 h). The range of tmax values for oral levetiracetam was greater (0.25–6.00 h); however, the median tmax for oral dosing (0.75 h) was similar to that for intravenous infusion. Geometric mean t was also similar between oral dosing (7.17 h) and intravenous infusion (7.13 h). Bioequivalence was demonstrated for AUC?, AUCt and Cmax (Table 2), with the 90 % CIs for the intravenous/oral ratio falling fully within the predefined ranges of 0.8–1.25 for AUC? and AUCt, and 0.7–1.43 for Cmax. 3.4 Multiple-Dose Infusion Levetiracetam Pharmacokinetics The overall pattern of the levetiracetam plasma concentration–time profile following 5 days of intravenous levetiracetam 1500 mg infusions (Figs. 2, 5) was consistent with the overall pattern observed following a single intravenous infusion at the same dose (Fig. 1). Mean plasma concentration increased rapidly throughout the infusion (i.e. up to and including 45 min), then decreased
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects Fig. 1 Levetiracetam geometric mean (95 % confidence interval) plasma concentration versus time (t) following 1500 mg singledose administration as oral tablets (triangles) or 45-min intravenous infusion (circles) over 36 h (main figure) and over 6 h (inset figure)
Fig. 2 Spaghetti plot of individual levetiracetam plasma concentrations versus time (t) following 1500 mg singledose administration as a 45-min intravenous infusion
biphasically following cessation of the infusion (i.e. a rapid distribution phase followed by an elimination phase). Geometric mean AUCs,ss for intravenous infusions administered every 12 h was similar to geometric mean AUC? after a single intravenous infusion (Table 3), and linear pharmacokinetics were confirmed by a linearity factor (0.948) very close to 1. Cmax,ss and AUCs,ss were in the range expected after multiple doses, based on their respective values following a single dose and on the t of 7.13 h. Based on the t, a theoretical accumulation of approximately 40 % would be expected after multiple doses. The observed accumulation of levetiracetam following multiple intravenous infusions,
based on Rmax and RAUC, was 18.0 and 43.5 %, respectively, which is consistent with the theoretical value. Steady state was achieved by approximately 24 h. 3.5 Safety In this population of healthy Chinese subjects, the majority of AEs were mild, and no serious AEs were reported. In Part A (single dose), the incidence and type of individual treatment-emergent AEs were similar following intravenous and oral administration; the most common AEs after both intravenous and oral dosing (percentage of subjects reporting each event) were somnolence (54 %
N. Toublanc et al. Fig. 3 Spaghetti plot of individual levetiracetam plasma concentrations versus time following 1500 mg single-dose administration as oral tablets
Table 1 Pharmacokinetic parameters for oral and intravenous infusion levetiracetam 1500 mg
Parameters
Oral levetiracetam (n = 24)
Intravenous infusion levetiracetam (n = 24)
AUCt (lgh/mL)
490.6 (9.2)
477.6 (8.8)a
AUC? (lgh/mL)
506.8 (9.5)
492.3 (9.2)a
AUCs,Day1 (lgh/mL)
329.5 (10.4)
327.7 (8.9)a
Cmax (lg/mL)
55.93 (32.8)
65.12 (12.5)a
C45,IV (lg/mL)
–
65.12 (12.5)a
CL/F and CLIV (L/h)
2.960 (9.5)
3.047 (9.2) 31.36 (13.2)
Vz/F and Vz,IV (L)
30.62 (14.2)
t (h)
7.17 (13.2)
7.13 (13.1)
tmax [h; median (range)]
0.75 (0.25–6.00)
0.73 (0.70–0.77)
Data are expressed as geometric mean (% CV) unless otherwise specified AUC? area under the plasma concentration–time curve from time zero to infinity, AUCt area under the plasma concentration–time curve from time zero to last quantifiable concentration, AUCs,Day1 area under the plasma concentration–time curve over the dosing interval (0–12 h) on day 1, Cmax maximum plasma concentration, C45,IV concentration at the end of the 45-min intravenous infusion, CL/F apparent total body clearance after oral administration, CLIV total body clearance after intravenous administration, CV coefficient of variation, tmax time to maximum plasma concentration, t terminal half-life, Vz/F volume of distribution after oral administration, Vz,IV volume of distribution after intravenous administration a
Dose-normalised parameters
intravenous and 58 % oral), dizziness (46 % intravenous and 42 % oral) and asthenia (17 % intravenous and 21 % oral). In Part B (multiple dose), the most common AEs in the intravenous levetiracetam group were somnolence (50 %), dizziness (39 %), diarrhoea, abdominal pain and nausea (each 11 %). Somnolence (33 %) and dizziness (17 %) were reported in the intravenous placebo group. No injection-site reactions were reported. AEs reported after multiple intravenous infusions were similar in incidence and type to those after single intravenous dosing. There were no clinically significant changes in vital signs, laboratory results, physical examination or electrocardiograms.
4 Discussion Overall, the pharmacokinetic results confirmed what has been previously demonstrated with levetiracetam [7, 8]. Based on data collected previously in Japanese subjects, exploratory simulations predicted that a 45-min intravenous infusion would be bioequivalent to the oral tablet at the same dose. This was demonstrated to be true in this population of healthy Chinese subjects, with 90 % CIs for AUC? and AUCt falling within the 80–125 % limit of acceptability for bioequivalence and the 90 % CIs for Cmax falling within the 70–143 % limit of acceptability. The Cmax,IV/Cmax,oral ratio of 1.16 in this study was also very close to the predicted
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects Table 2 Bioequivalence of oral and intravenous infusion levetiracetam: ANOVA (n = 24) Parameters
Levetiracetam 1500 mg, orala
Levetiracetam 1500 mg, intravenous infusiona
Point estimate intravenous/oral ratio
90 % CI
AUCt (lgh/mL)
491.2
478.2b
0.9736
0.9461–1.002
507.0
b
0.9713
0.9430–1.001
6.0
1.164
1.005–1.286
20.2
AUC? (lgh/mL) Cmax (lg/mL)
57.50
492.5
66.96b
CVres (%) 5.8
ANOVA analysis of variance, AUC? area under the plasma concentration–time curve from time zero to infinity, AUCt area under the plasma concentration–time curve from time zero to last quantifiable concentration, Cmax maximum plasma concentration, CI confidence interval, CVres ANOVA residual error, representing intrasubject variability a
Least-squares mean from the ANOVA
b
Dose-normalised parameters
Fig. 4 Levetiracetam geometric mean (95 % confidence interval) dosenormalised plasma concentration–time (t) profile following levetiracetam 1500 mg 45-min intravenous infusion every 12 h for 5 days
Cmax,IV/Cmax,oral ratio of 1.14 from the simulations of a 45-min infusion based on the Japanese data [6]. The geometric mean t and median tmax were very similar between the intravenous infusion and oral levetiracetam groups (7.13 and 7.17 h, respectively for t, and 0.733 and 0.750 h, respectively for tmax). As expected with a standardised intravenous infusion time, the range of tmax values observed across subjects was narrow (range 0.70–0.77 h), while a wider range in tmax values was observed following oral administration (range 0.25–6.00 h). Limited deviations in dose rather than in duration of infusion were authorised to accurately determine Cmax at the end of the planned 45-min infusion. This means that the infusion was stopped at the end of 45 min even if the entire volume of levetiracetam had not been administered. While this practice did result in some actual intravenous levetiracetam doses being slightly lower than specified in the protocol, this did not adversely impact the pharmacokinetic analysis since the pharmacokinetics of levetiracetam are dose proportional.
The second part of the study demonstrated that after multiple intravenous infusions of levetiracetam 1500 mg (twice daily dosing over 4.5 days), geometric mean AUCs,ss was similar compared with geometric mean AUC? after single intravenous infusion. Linear pharmacokinetics were confirmed by a linearity factor value very close to 1 (linearity factor: 0.948). As expected after multiple intravenous infusions, Cmax and AUCs,ss were higher compared with values following single-dose administration. Rmax and RAUC values of 118.0 and 143.5 %, respectively, are the consequence of accumulation of levetiracetam, which is expected based on the single-dose pharmacokinetics and the interval of administration. Based on the t after a single dose and a twice-daily dosing, a theoretical accumulation of approximately 40 % would be expected after multiple doses, which is consistent with the calculated values. Overall, levetiracetam was well tolerated and no new safety findings were identified in this study. The AE profile was similar between intravenous infusion and oral administration, between single and multiple intravenous dosing,
N. Toublanc et al. Fig. 5 Spaghetti plot of levetiracetam plasma concentration–time (t) profile following levetiracetam 1500 mg 45-min intravenous infusion every 12 h for 5 days
Table 3 Levetiracetam pharmacokinetic parameters after a single intravenous infusion and at steady state after intravenous infusion every 12 h: ANOVA (n = 18) Levetiracetam 1500 mg
Least-squares meansa (95 % CI)
AUCs,ss (lgh/mL)
Steady state
475.6 (458.6–493.3)
AUC? (lgh/mL)
Single dose
501.7 (483.7–520.3)
AUCs,ss (lgh/mL)
Steady state
475.6 (457.5–494.5)
AUCs,Day1 (lgh/mL)
Single dose
331.5 (318.9–344.6)
Cmax,ss (lg/mL)
Steady state
77.44 (74.15–80.87)
Cmax,Day1 (lg/mL)
Single dose
65.60 (62.81–68.51)
Parameter
Linearity factor
RAUC
Rmax
Point estimate multiple/single ratio (90 % CI)
CVres (%)
0.9481 (0.9085–0.9894)
7.4
1.435 (1.371–1.501)
7.8
1.180 (1.122–1.242)
8.7
ANOVA analysis of variance, AUC? area under the plasma concentration–time curve extrapolated to infinity, AUCs,Day1 area under the plasma concentration–time curve during the dosing interval s (0–12 h) on day 1, AUCs,ss area under the plasma concentration–time curve during the dosing interval s after last intravenous dose (steady state, CI confidence interval, Cmax,ss maximum concentration (steady state), Cmax,Day1 maximum concentration (day 1), CVres ANOVA residual error, representing intrasubject variability, RAUC accumulation ratio of AUC, Rmax accumulation ratio of Cmax a
Dose-normalised parameters
and between levetiracetam and placebo, with no injectionsite reactions on intravenous infusion.
5 Conclusions Bioequivalence of intravenous infusion of levetiracetam 1500 mg (over 45 min) and oral levetiracetam 1500 mg tablets was established in healthy Chinese subjects. Comparison of AUCs versus AUC? values following multiple and single intravenous infusions of levetiracetam 1500 mg
demonstrated linear pharmacokinetics. Cmax and AUCs of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the t of levetiracetam. The extent of accumulation of levetiracetam following 4.5 days of twice-daily dosing was as expected based on the day 1 pharmacokinetics. Acknowledgments The authors thank Fiona Swain (Mediwrite Ltd, UK) for providing medical writing support funded by UCB Pharma, and Barbara Pelgrims and Azita Tofighy (UCB Pharma) for editorial support and coordinating the manuscript development process.
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects Compliance with Ethical Standards Funding This study was funded by UCB Pharma, who were involved in the design and conduct of the study, and collection, management, and analysis of the data. Conflicts of interest Nathalie Toublanc, Xinlu Du, Armel Stockis, Pritibha Singh and Robert Chan were employees of UCB Pharma at the time the study was conducted. Yun Liu and Qian Chen were employees of the Clinical Research Unit at Shanghai Xuhui Central Hospital, which conducted the clinical phase of the study for UCB Pharma, and have no conflicts of interest.
3.
4.
5. Ethical approval The research followed the ethical principles for medical research set forth in the Declaration of Helsinki 1964, as modified by subsequent revisions. Approval for the study was obtained from an Independent Review Board and informed consent was obtained in writing from all participants prior to initiating any study-related medical procedure.
6.
7.
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data from randomized adjunctive therapy trials. Epilepsy Res. 2003;53:47–56. Ramael S, De Smedt F, Toublanc N, Otoul C, Boulanger P, Riethuisen JM, et al. 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. Clin Ther. 2006;28:734–44. Ramael S, Daoust A, Otoul C, Toublanc N, Troenaru M, Lu Z, et al. Levetiracetam intravenous infusion: a randomized, placebocontrolled safety and pharmacokinetic study. Epilepsia. 2006;47(7):1128–35. Baulac M, Brodie MJ, Elger CE, Krakow K, Stockis A, Meyvisch P, et al. Levetiracetam intravenous infusion as an alternative to oral dosing in patients with partial-onset seizures. Epilepsia. 2007;48(3):589–92. Yamamoto J, Toublanc N, Kumagai Y, Stockis A. Levetiracetam pharmacokinetics in Japanese subjects with renal impairment. Clin Drug Investig. 2014;34:819–28. Stockis A, Lu S, Tonner F, Otoul C. Clinical pharmacology of levetiracetam for the treatment of epilepsy. Expert Rev Clin Pharmacol. 2009;2(4):339–50. Zhao Q, Jiang J, Li XM, Lu Z, Hu P. Single-dose pharmacokinetics of levetiracetam in healthy Chinese male subjects. Br J Clin Pharmacol. 2007;63(5):614–7.
ORIGINAL RESEARCH ARTICLE
Pharmacokinetics, Safety and Bioequivalence of Levetiracetam Intravenous Infusion and Oral Tablets in Healthy Chinese Subjects Nathalie Toublanc1 • Xinlu Du2 • Yun Liu3 • Qian Chen3 • Pritibha Singh4,6 Robert Chan5,7 • Armel Stockis1
•
Ó Springer International Publishing Switzerland 2015
Abstract Background and Objective Levetiracetam is available in China as adjunctive oral therapy for partial-onset seizures. This study was conducted to evaluate the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg (Part A), and to assess the pharmacokinetics of multiple-dose intravenous infusion at the same dose (Part B) in healthy Chinese subjects. Methods Part A was an open-label, crossover comparison (intravenous vs. oral), while Part B was a double-blind, parallel-group study of intravenous levetiracetam versus intravenous placebo administered for 5 days. Results Bioequivalence was demonstrated between the 45-min intravenous infusion and oral tablets, with geometric mean area under the plasma concentration–time curve (AUC) from time 0 to infinity (AUC?) 492.3 and 506.8 lgh/mL, and geometric mean maximum concentration (Cmax) 65.12 and 55.93 lg/mL for intravenous infusion and oral dosing, respectively. Linear pharmacokinetics were demonstrated (geometric least-squares mean AUC during the dosing interval s at steady state (AUCs,ss) 475.6 lgh/mL; geometric & Nathalie Toublanc [email protected] 1
UCB Pharma, Chemin du Foriest, 1420 Braine-l’Alleud, Belgium
2
UCB Pharma, Shanghai, China
3
Shanghai Xuhui Central Hospital, Shanghai, China
4
UCB Pharma, Monheim, Germany
5
UCB Pharma, Tokyo, Japan
6
Present Address: Hexal AG, Sandoz Biopharmaceuticals, Hlozkirchen, Germany
7
Present Address: Biogen Idec Japan Ltd, Tokyo, Japan
least-squares mean AUC? after single dose 501.7 lgh/mL; linearity factor = 0.948). Geometric mean Cmax (77.44 lg/ mL) and AUCs,ss (475.6 lgh/mL) of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the terminal half-life of levetiracetam after a single dose (7.13 h). A theoretical accumulation of approximately 40 % would be expected after multiple doses, which is consistent with the calculated accumulation of 18.0 and 43.5 % (Rmax and RAUC, respectively). Conclusions Intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects and is a suitable alternative for levetiracetam administration in patients who are temporarily unable to take their medication orally. Key Points Although levetiracetam is usually administered orally, intravenous administration provides an important alternative for patients who are temporarily unable to take oral medication. This study evaluated the bioequivalence between single-dose intravenous infusion and oral levetiracetam 1500 mg, and assessed the pharmacokinetics of multiple-dose intravenous infusion at the same dose in healthy Chinese subjects. Results from this study were consistent with historical data in other ethnic groups and demonstrated that intravenous infusion of levetiracetam is bioequivalent to oral levetiracetam in healthy Chinese subjects.
N. Toublanc et al.
1 Introduction Levetiracetam [KeppraÒ; (-)-(S)-a-ethyl-2-oxo-1-pyrrolidine acetamide], an antiepileptic drug (AED), is available in China as adjunctive oral therapy for adults and children (from 1 month of age) with partial-onset seizures. Levetiracetam is rapidly absorbed, with peak plasma concentrations within 0.5–2.3 h after dosing, and has linear pharmacokinetics [1–3]. Although levetiracetam is usually administered orally, intravenous administration provides an important alternative for patients who are temporarily unable to take oral medication due to medical conditions associated with swallowing problems, upper gastrointestinal intolerance or malabsorption (e.g. altered state of consciousness, acute upper gastrointestinal dysfunction, or having to comply with a nil-by-mouth regimen preoperatively or postoperatively). Intravenous administration enables the patient to continue levetiracetam treatment and minimises the risk of destabilising seizure control when oral administration is temporarily infeasible. This study was conducted to evaluate the bioequivalence of intravenous levetiracetam and oral levetiracetam (Part A), and to assess the pharmacokinetics of multiple-dose intravenous levetiracetam (Part B) in healthy Chinese subjects. The safety of intravenous levetiracetam was assessed in both parts and compared with placebo over a 5-day treatment period in Part B. The study was performed to support a submission for the intravenous formulation of levetiracetam in China, as requested by the China Food and Drug Administration (CFDA). The dose selected for this study reflected the maximum recommended dose per intake/administration based on current labelling (1500 mg twice daily, i.e. 3000 mg/day). The dose of 1500 mg has also been used in previous bioequivalence studies [3–6]. A crossover design was chosen for the bioequivalence part of the study (Part A) since it allowed within-subject comparisons of the two levetiracetam formulations. A treatment duration of 5 days was chosen for the multiple-dose part of the study (Part B) because steady state is reached within 2 days with levetiracetam and because most intravenous AED courses are relatively short in duration.
2 Methods This clinical study was conducted between May and July 2012 in the Clinical Research Unit of Shanghai Xuhui Central Hospital, China. The study consisted of two parts. Part A [NCT01618903] was an open-label, crossover comparison of intravenous infusion versus oral 1500 mg
levetiracetam, while Part B [NCT01618877] was a doubleblind, parallel-group comparison of multiple-dose intravenous infusion levetiracetam versus placebo. This research followed the ethical principles for medical research set forth in the Declaration of Helsinki 1964, as modified by subsequent revisions. Approval for the study was obtained from an Independent Review Board and informed consent was obtained in writing from all participants prior to initiating any study-related medical procedure. 2.1 Study Population The study population consisted of 24 healthy subjects (12 males and 12 females). To be included in the study, subjects had to be aged 18–40 years and of Chinese descent, with all four grandparents born in China. All participants had to be considered in good health, with a bodyweight C50 kg and body mass index (BMI) between 19 and 24 kg/ m2. They were stratified by sex and randomised to one of two treatment sequences in Part A (12 received intravenous levetiracetam followed by oral levetiracetam, and 12 received oral levetiracetam followed by intravenous levetiracetam). In Part B, subjects were randomised to intravenous levetiracetam (n = 18) or intravenous placebo (n = 6). 2.2 Study Design 2.2.1 Bioequivalence Study Design—Part A Part A was open-label. All participants received a single dose of each treatment, with a 7-day washout between treatments to exclude any carryover effects. The treatments were (1) levetiracetam 1500 mg (500 mg/5 mL vials) administered as a 45-min intravenous infusion diluted in 100 mL 0.9 % saline solution, and (2) levetiracetam 3 9 500 mg tablets. The oral dose was taken with 200 mL of water. The intravenous formulation consisted of sealed vials containing approximately 5.4 mL of levetiracetam 100 mg/mL solution of sterile buffered saline. For intravenous administration, a total 15.0 mL of levetiracetam intravenous solution from three vials was transferred by syringe into a 100 mL pouch of 0.9 % sterile saline. The solution was infused over a 45-min period through a venous catheter. Infusion time was standardised at 45 min, irrespective of whether the whole dose had been administered; this was done in order to accurately determine maximum plasma concentration (Cmax). Blood samples were taken for pharmacokinetic analysis at the following timepoints: predose and at 15, 30, and 45 min, and 1, 1.5, 2, 3, 6, 9, 12, 24, and 36 h after oral
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects
dose administration or after the start of the intravenous infusion. 2.2.2 Multiple-Dose Pharmacokinetic Study Design—Part B Subjects who completed Part A were randomised to one of two 45-min intravenous infusion treatments in Part B: levetiracetam 1500 mg (500 mg/5 mL vials) diluted in 100 mL 0.9 % saline solution or placebo (15 mL 0.9 % saline solution) added to 100 mL 0.9 % saline solution. Part B treatment began 48 h after completion of the last treatment in Part A. Part B infusions were administered every 12 h for 4.5 days (a total of nine infusions). Only the pharmacist dispensing the prescription was unblinded; as such he did not participate in any other study activities. Measures were taken to ensure that levetiracetam and placebo were indistinguishable in appearance; a total 15.0 mL of levetiracetam or placebo solution from three vials was transferred by syringe into a 100 mL pouch of 0.9 % sterile saline for infusion. For each of the first eight infusions in Part B, blood samples were taken for pharmacokinetic analysis predose and at 45 min, i.e. at the end of the infusion (a total of 16 plasma samples). For the last infusion, blood samples were obtained at predose and at 15, 30, and 45 min, and 1, 1.5, 2, 3, 6, 9, 12, 24, and 36 h after the start of the infusion (13 samples). 2.3 Safety Safety was evaluated throughout the study by monitoring adverse events (AEs), laboratory parameters, and vital signs, and by conducting electrocardiograms and physical examinations. 2.4 Analytical Determinations Plasma levetiracetam determinations were performed by Frontage Laboratories (Shanghai) Co., Ltd, Shanghai, China. The assay method was based on liquid chromatography with triple-stage quadrupole mass spectrometric detection (LC/MS/MS) and used a Sciex API4000 instrument with Turbo Ion Spray interface (AB Sciex, Framingham, MA, USA). Levetiracetam-D6 was used as the internal standard. Levetiracetam and internal standard were extracted from plasma by solid-phase extraction using Waters Sep-PakÒ (C18 100 mg) 96-well plates (Waters Corporation, Milford, MA, USA). Reversed-phase highperformance liquid chromatography separation was achieved using a Waters SunfireTM C18 column (50 mm 9 2.1 mm internal diameter, 3.5 lm particle size) protected by a 10-mm guard column. The mobile phase was a gradient of water and acetonitrile containing 0.1 %
trifluoroacetic acid adjusted at pH 2.5. Detection was set at mass transitions of 170.9 ? 125.9 m/z for levetiracetam and 177.0 ? 132.0 m/z for levetiracetam-D6 in total ion scan, positive mode. The method was validated in human plasma in the concentration range from 0.1 to 100.00 lg/mL. The intrarun precision and accuracy of the analytical method were evaluated after replicate analysis (n = 6 at each concentration level) of validation samples prepared in human Liheparinized plasma at five concentration levels: lower limit of quantification (0.1 lg/mL), low concentration (0.3 lg/ mL), mid-range concentration (25.0 lg/mL), high concentration (80.0 lg/mL) and upper limit of quantification (100.0 lg/mL). Three intra-run determinations were performed over three different runs. An independent calibration curve was freshly prepared for each run. Intermediate precision, expressed as a coefficient of variation, was 10.7, 5.9, 2.4, 2.1, and 3.7 %, respectively; recovery, expressed as a percentage of nominal concentration, was 103.0, 107.7, 107.4, 100.4, and 100.9 %, respectively. 2.5 Pharmacokinetic and Statistical Analysis The pharmacokinetic and statistical calculations were performed using Phoenix WinNonlin version 6.2 (Certara Inc., St. Louis, MO, USA) and SAS version 9.1.3 (SAS Institute Inc., Cary, NC, USA), respectively. Pharmacokinetic parameters were derived by noncompartmental analysis, using actual sampling times. Parameters calculated for levetiracetam in Part A included Cmax, time to Cmax (tmax), plasma concentration at the end of the 45-min infusion (C45,IV), area under the plasma concentration-versus-time curve from time zero to the last quantifiable concentration (AUCt), AUC over the dosing interval (s) 0–12 h (AUCs,Day1), AUC from time zero to infinity (AUC?), terminal half-life (t), total body clearance (CLIV) and volume of distribution (Vz,IV) after intravenous infusion, as well as apparent total body clearance (CL/F) and volume of distribution (Vz/F) after oral administration. Parameters calculated for levetiracetam in Part B included Cmax, AUC during the dosing interval s after the last intravenous dose at steady state (AUCs,ss), minimum plasma concentration after intravenous infusion (Cmin) and t. Study staff were instructed to adhere to the 45-min intravenous infusion time even if the entire volume of levetiracetam had not been administered at the end of 45 min; therefore, analysis was conducted on dose-normalised and nondose-normalised parameters. For the primary pharmacokinetic parameters (AUC?, AUCt, and Cmax), the point estimates and the 90 % confidence intervals (CIs) of the geometric mean ratio between the intravenous and oral tablet formulations were computed. The calculations were made using the least-squares
N. Toublanc et al.
means and the root mean square of error from an analysis of variance (ANOVA) of the log-transformed (natural) data with subsequent exponential transformation (i.e. back transformation). Intrasubject variability was also estimated from the ANOVA. The ANOVA model included factors of treatment, period, and sequence as fixed effects, and subject nested within sequence as the random effect. Bioequivalence was to be concluded if the 90 % CIs for the intravenous/oral ratio were fully included in the acceptance range for bioequivalence of 0.8–1.25 for AUC? and AUCt, and 0.7–1.43 for Cmax. Single- and multiple-dose pharmacokinetics were compared by calculating the linearity factor and the accumulation ratios of AUC (RAUC) and Cmax (Rmax). The linearity factor was calculated as the ratio of AUCs,ss and AUC? after single-dose administration. The point estimates and 90 % CIs of the geometric mean ratio between single dose and multiple doses were computed using the least squares means and the root mean square of error from an ANOVA of the log-transformed (natural) data with subsequent exponential transformation (i.e. back transformation). Intrasubject variability was also estimated from the ANOVA. The ANOVA model included factors of treatment (single or multiple doses) and subject as fixed effects. Similarly, the AUCs,ss in Part B versus AUCs,Day1 after single-dose administration in Part A were used to calculate the RAUC. The Rmax was assessed by comparing Cmax at steady state (Cmax,ss) with Cmax,Day1 after single-dose administration. For sample size estimation, the intrasubject coefficient of variation was assumed to be 3.6 % for AUCt and 22.8 % for Cmax. Based on a true value of 1.14 for the Cmax ratio, 20 subjects were required to achieve 90 % power for the assessment of bioequivalence at a significance level of a = 0.05. A sample size of 24 subjects was chosen, to take into account possible dropouts.
3 Results 3.1 Study Population The 24 subjects (12 males, 12 females) had a mean age of 24.8 years (range 19–31 years), mean height of 164.1 cm (range 153–172 cm), mean bodyweight of 58.76 kg (range 50.3–69.5 kg), and mean BMI of 21.79 kg/m2 (range 19.1–24.0 kg/m2). With regard to sex, no differences were noted for age and BMI between male and female subjects; mean height and weight were higher in male subjects compared with female subjects. Given stratification by sex, the groups in both Parts A and B were well balanced, with no notable differences in demographics between the groups.
3.2 Study Drug Exposure The actual intravenous dose in Part A and the final intravenous dose in Part B differed from the protocol dose (1500 mg) by more than 10 % for three subjects. Intravenous pharmacokinetic parameters were therefore dosenormalised. As results from analyses conducted on dosenormalised and nondose-normalised parameters were similar, only dose-normalised parameters were presented. 3.3 Comparison of Single-Dose Intravenous and Oral Levetiracetam Overall, levetiracetam geometric mean dose-normalised plasma concentration-versus-time profiles for oral and intravenous infusion were similar (Fig. 1). During the first 45 min, geometric mean plasma concentration increased faster for intravenous infusion, reaching a higher mean concentration at 45 min (approximately 65 lg/mL) than for oral dosing at the same timepoint (approximately 40 lg/mL). Spaghetti plots for single intravenous and oral doses are provided in Figs. 2 and 3, respectively. Geometric mean AUC? was similar between intravenous infusion (492.3 lgh/mL) and oral tablet dosing (506.8 lgh/mL) (Table 1). Geometric mean Cmax after intravenous infusion (65.12 lg/mL) was 16 % higher than after oral tablet administration (55.93 lg/mL). The range of Cmax values for intravenous infusion was within the range for oral administration. Since study staff were instructed to stop the intravenous infusion at 0.75 h (45 min), irrespective of whether the whole dose had been given, median tmax for the intravenous infusion was 0.73 h (range 0.70–0.77 h). The range of tmax values for oral levetiracetam was greater (0.25–6.00 h); however, the median tmax for oral dosing (0.75 h) was similar to that for intravenous infusion. Geometric mean t was also similar between oral dosing (7.17 h) and intravenous infusion (7.13 h). Bioequivalence was demonstrated for AUC?, AUCt and Cmax (Table 2), with the 90 % CIs for the intravenous/oral ratio falling fully within the predefined ranges of 0.8–1.25 for AUC? and AUCt, and 0.7–1.43 for Cmax. 3.4 Multiple-Dose Infusion Levetiracetam Pharmacokinetics The overall pattern of the levetiracetam plasma concentration–time profile following 5 days of intravenous levetiracetam 1500 mg infusions (Figs. 2, 5) was consistent with the overall pattern observed following a single intravenous infusion at the same dose (Fig. 1). Mean plasma concentration increased rapidly throughout the infusion (i.e. up to and including 45 min), then decreased
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects Fig. 1 Levetiracetam geometric mean (95 % confidence interval) plasma concentration versus time (t) following 1500 mg singledose administration as oral tablets (triangles) or 45-min intravenous infusion (circles) over 36 h (main figure) and over 6 h (inset figure)
Fig. 2 Spaghetti plot of individual levetiracetam plasma concentrations versus time (t) following 1500 mg singledose administration as a 45-min intravenous infusion
biphasically following cessation of the infusion (i.e. a rapid distribution phase followed by an elimination phase). Geometric mean AUCs,ss for intravenous infusions administered every 12 h was similar to geometric mean AUC? after a single intravenous infusion (Table 3), and linear pharmacokinetics were confirmed by a linearity factor (0.948) very close to 1. Cmax,ss and AUCs,ss were in the range expected after multiple doses, based on their respective values following a single dose and on the t of 7.13 h. Based on the t, a theoretical accumulation of approximately 40 % would be expected after multiple doses. The observed accumulation of levetiracetam following multiple intravenous infusions,
based on Rmax and RAUC, was 18.0 and 43.5 %, respectively, which is consistent with the theoretical value. Steady state was achieved by approximately 24 h. 3.5 Safety In this population of healthy Chinese subjects, the majority of AEs were mild, and no serious AEs were reported. In Part A (single dose), the incidence and type of individual treatment-emergent AEs were similar following intravenous and oral administration; the most common AEs after both intravenous and oral dosing (percentage of subjects reporting each event) were somnolence (54 %
N. Toublanc et al. Fig. 3 Spaghetti plot of individual levetiracetam plasma concentrations versus time following 1500 mg single-dose administration as oral tablets
Table 1 Pharmacokinetic parameters for oral and intravenous infusion levetiracetam 1500 mg
Parameters
Oral levetiracetam (n = 24)
Intravenous infusion levetiracetam (n = 24)
AUCt (lgh/mL)
490.6 (9.2)
477.6 (8.8)a
AUC? (lgh/mL)
506.8 (9.5)
492.3 (9.2)a
AUCs,Day1 (lgh/mL)
329.5 (10.4)
327.7 (8.9)a
Cmax (lg/mL)
55.93 (32.8)
65.12 (12.5)a
C45,IV (lg/mL)
–
65.12 (12.5)a
CL/F and CLIV (L/h)
2.960 (9.5)
3.047 (9.2) 31.36 (13.2)
Vz/F and Vz,IV (L)
30.62 (14.2)
t (h)
7.17 (13.2)
7.13 (13.1)
tmax [h; median (range)]
0.75 (0.25–6.00)
0.73 (0.70–0.77)
Data are expressed as geometric mean (% CV) unless otherwise specified AUC? area under the plasma concentration–time curve from time zero to infinity, AUCt area under the plasma concentration–time curve from time zero to last quantifiable concentration, AUCs,Day1 area under the plasma concentration–time curve over the dosing interval (0–12 h) on day 1, Cmax maximum plasma concentration, C45,IV concentration at the end of the 45-min intravenous infusion, CL/F apparent total body clearance after oral administration, CLIV total body clearance after intravenous administration, CV coefficient of variation, tmax time to maximum plasma concentration, t terminal half-life, Vz/F volume of distribution after oral administration, Vz,IV volume of distribution after intravenous administration a
Dose-normalised parameters
intravenous and 58 % oral), dizziness (46 % intravenous and 42 % oral) and asthenia (17 % intravenous and 21 % oral). In Part B (multiple dose), the most common AEs in the intravenous levetiracetam group were somnolence (50 %), dizziness (39 %), diarrhoea, abdominal pain and nausea (each 11 %). Somnolence (33 %) and dizziness (17 %) were reported in the intravenous placebo group. No injection-site reactions were reported. AEs reported after multiple intravenous infusions were similar in incidence and type to those after single intravenous dosing. There were no clinically significant changes in vital signs, laboratory results, physical examination or electrocardiograms.
4 Discussion Overall, the pharmacokinetic results confirmed what has been previously demonstrated with levetiracetam [7, 8]. Based on data collected previously in Japanese subjects, exploratory simulations predicted that a 45-min intravenous infusion would be bioequivalent to the oral tablet at the same dose. This was demonstrated to be true in this population of healthy Chinese subjects, with 90 % CIs for AUC? and AUCt falling within the 80–125 % limit of acceptability for bioequivalence and the 90 % CIs for Cmax falling within the 70–143 % limit of acceptability. The Cmax,IV/Cmax,oral ratio of 1.16 in this study was also very close to the predicted
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects Table 2 Bioequivalence of oral and intravenous infusion levetiracetam: ANOVA (n = 24) Parameters
Levetiracetam 1500 mg, orala
Levetiracetam 1500 mg, intravenous infusiona
Point estimate intravenous/oral ratio
90 % CI
AUCt (lgh/mL)
491.2
478.2b
0.9736
0.9461–1.002
507.0
b
0.9713
0.9430–1.001
6.0
1.164
1.005–1.286
20.2
AUC? (lgh/mL) Cmax (lg/mL)
57.50
492.5
66.96b
CVres (%) 5.8
ANOVA analysis of variance, AUC? area under the plasma concentration–time curve from time zero to infinity, AUCt area under the plasma concentration–time curve from time zero to last quantifiable concentration, Cmax maximum plasma concentration, CI confidence interval, CVres ANOVA residual error, representing intrasubject variability a
Least-squares mean from the ANOVA
b
Dose-normalised parameters
Fig. 4 Levetiracetam geometric mean (95 % confidence interval) dosenormalised plasma concentration–time (t) profile following levetiracetam 1500 mg 45-min intravenous infusion every 12 h for 5 days
Cmax,IV/Cmax,oral ratio of 1.14 from the simulations of a 45-min infusion based on the Japanese data [6]. The geometric mean t and median tmax were very similar between the intravenous infusion and oral levetiracetam groups (7.13 and 7.17 h, respectively for t, and 0.733 and 0.750 h, respectively for tmax). As expected with a standardised intravenous infusion time, the range of tmax values observed across subjects was narrow (range 0.70–0.77 h), while a wider range in tmax values was observed following oral administration (range 0.25–6.00 h). Limited deviations in dose rather than in duration of infusion were authorised to accurately determine Cmax at the end of the planned 45-min infusion. This means that the infusion was stopped at the end of 45 min even if the entire volume of levetiracetam had not been administered. While this practice did result in some actual intravenous levetiracetam doses being slightly lower than specified in the protocol, this did not adversely impact the pharmacokinetic analysis since the pharmacokinetics of levetiracetam are dose proportional.
The second part of the study demonstrated that after multiple intravenous infusions of levetiracetam 1500 mg (twice daily dosing over 4.5 days), geometric mean AUCs,ss was similar compared with geometric mean AUC? after single intravenous infusion. Linear pharmacokinetics were confirmed by a linearity factor value very close to 1 (linearity factor: 0.948). As expected after multiple intravenous infusions, Cmax and AUCs,ss were higher compared with values following single-dose administration. Rmax and RAUC values of 118.0 and 143.5 %, respectively, are the consequence of accumulation of levetiracetam, which is expected based on the single-dose pharmacokinetics and the interval of administration. Based on the t after a single dose and a twice-daily dosing, a theoretical accumulation of approximately 40 % would be expected after multiple doses, which is consistent with the calculated values. Overall, levetiracetam was well tolerated and no new safety findings were identified in this study. The AE profile was similar between intravenous infusion and oral administration, between single and multiple intravenous dosing,
N. Toublanc et al. Fig. 5 Spaghetti plot of levetiracetam plasma concentration–time (t) profile following levetiracetam 1500 mg 45-min intravenous infusion every 12 h for 5 days
Table 3 Levetiracetam pharmacokinetic parameters after a single intravenous infusion and at steady state after intravenous infusion every 12 h: ANOVA (n = 18) Levetiracetam 1500 mg
Least-squares meansa (95 % CI)
AUCs,ss (lgh/mL)
Steady state
475.6 (458.6–493.3)
AUC? (lgh/mL)
Single dose
501.7 (483.7–520.3)
AUCs,ss (lgh/mL)
Steady state
475.6 (457.5–494.5)
AUCs,Day1 (lgh/mL)
Single dose
331.5 (318.9–344.6)
Cmax,ss (lg/mL)
Steady state
77.44 (74.15–80.87)
Cmax,Day1 (lg/mL)
Single dose
65.60 (62.81–68.51)
Parameter
Linearity factor
RAUC
Rmax
Point estimate multiple/single ratio (90 % CI)
CVres (%)
0.9481 (0.9085–0.9894)
7.4
1.435 (1.371–1.501)
7.8
1.180 (1.122–1.242)
8.7
ANOVA analysis of variance, AUC? area under the plasma concentration–time curve extrapolated to infinity, AUCs,Day1 area under the plasma concentration–time curve during the dosing interval s (0–12 h) on day 1, AUCs,ss area under the plasma concentration–time curve during the dosing interval s after last intravenous dose (steady state, CI confidence interval, Cmax,ss maximum concentration (steady state), Cmax,Day1 maximum concentration (day 1), CVres ANOVA residual error, representing intrasubject variability, RAUC accumulation ratio of AUC, Rmax accumulation ratio of Cmax a
Dose-normalised parameters
and between levetiracetam and placebo, with no injectionsite reactions on intravenous infusion.
5 Conclusions Bioequivalence of intravenous infusion of levetiracetam 1500 mg (over 45 min) and oral levetiracetam 1500 mg tablets was established in healthy Chinese subjects. Comparison of AUCs versus AUC? values following multiple and single intravenous infusions of levetiracetam 1500 mg
demonstrated linear pharmacokinetics. Cmax and AUCs of intravenous infusion levetiracetam 1500 mg after multiple doses were within the expected range, based on their respective single-dose values and the t of levetiracetam. The extent of accumulation of levetiracetam following 4.5 days of twice-daily dosing was as expected based on the day 1 pharmacokinetics. Acknowledgments The authors thank Fiona Swain (Mediwrite Ltd, UK) for providing medical writing support funded by UCB Pharma, and Barbara Pelgrims and Azita Tofighy (UCB Pharma) for editorial support and coordinating the manuscript development process.
Levetiracetam IV/Oral Bioequivalence in Healthy Chinese Subjects Compliance with Ethical Standards Funding This study was funded by UCB Pharma, who were involved in the design and conduct of the study, and collection, management, and analysis of the data. Conflicts of interest Nathalie Toublanc, Xinlu Du, Armel Stockis, Pritibha Singh and Robert Chan were employees of UCB Pharma at the time the study was conducted. Yun Liu and Qian Chen were employees of the Clinical Research Unit at Shanghai Xuhui Central Hospital, which conducted the clinical phase of the study for UCB Pharma, and have no conflicts of interest.
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5. Ethical approval The research followed the ethical principles for medical research set forth in the Declaration of Helsinki 1964, as modified by subsequent revisions. Approval for the study was obtained from an Independent Review Board and informed consent was obtained in writing from all participants prior to initiating any study-related medical procedure.
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