Single-dose pharmacokinetics of levetiracetam in healthy Chinese male subjects

Abstract

What is already known about this subject

• Levetiracetam has been evaluated for epilepsy since 1992.

• Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment.

• Although this antiepileptic has been well studied in Western countries, this paper describes the first such trial of the drug in a Chinese population.

What this study adds

• Information is given on the pharmacokinetics, dose proportionality, safety and tolerability profile of levetiracetam in healthy male Chinese volunteers, and the results are compared with published data obtained in White subjects.

• The pharmacokinetics and the pattern of adverse events of levetiracetam in Chinese subjects are similar to the data reported in White subjects.

Aims

The main aims of this study were to evaluate the pharmacokinetics of levetiracetam in healthy male Chinese volunteers and to assess the dose proportionality between the 500-mg and 1500-mg single doses.

Methods

This was a randomized, single-centre, single-dose, two-way crossover study. Twenty-six healthy male Chinese subjects were enrolled. All subjects received a single dose of 500 mg or 1500 mg levetiracetam tablet(s) on the dosing day, and the wash-out period was 7 days. Blood was obtained for a 36-h pharmacokinetic evaluation.

Results

Following single-dose administration of 500 mg and 1500 mg of levetiracetam, the median t_max was 0.5 and 0.5 h; t_1/2 was 7.3 ± 0.8 and 7.3 ± 0.7 h; C_max was 13.6 ± 3.2 and 47.1 ± 12.1 µg ml⁻¹; AUC_0–∞ was 109.3 ± 14.1 and 340.4 ± 50.6 µg h⁻¹ ml⁻¹; and AUC_0–t was 105.7 ± 13.3 and 329.0 ± 47.9 µg h⁻¹ ml⁻¹, respectively.

Conclusions

Both C_max and AUCs were dose-proportional over the range of 500–1500 mg. The pharmacokinetic data obtained in these Chinese subjects were similar to the historical data from a matched group of White subjects.

Introduction

Levetiracetam [(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide] is a novel antiepileptic drug with a unique mechanism of action. It was found to be well tolerated and effective when used as an adjunctive treatment in adults and children with partial-onset seizures [1–6]. One major advantage of levetiracetam is that it has minimal potential for pharmacokinetic drug interactions. This is due to the minimal metabolism that does not utilize hepatic cytochrome P450 enzymes, and low protein binding [7]. Neither levetiracetam nor its major metabolite formed via hydrolysis is bound significantly to plasma proteins (<10%) [8].

White pharmacokinetic data show that levetiracetam is rapidly and almost completely absorbed after oral administration. The oral bioavailability of levetiracetam tablets is close to 100%. The maximal plasma concentration (C_max) is generally reached within 1 h after administration in fasting subjects. After single-dose oral administration, C_max and area under the curve (AUC) are proportional to the dose given (range 500–5000 mg) [9]. The apparent volume of distribution (V_z/F) is in the range of 0.5–0.7 l kg⁻¹. The major route of levetiracetam excretion is via the urine, accounting for a mean of 95% of the administered dose. The renal clearance (CL_R) is approximately 0.6 ml min⁻¹ kg⁻¹. The half-life (t_1/2) of the compound is 7.2 ± 1.1 h in young healthy volunteers, with a slightly shorter half-life in females. The longer t_1/2 (10–11 h) in elderly subjects is due to an age-related decline in renal function [10]. The apparent clearance (CL/F) is 0.96 ml min⁻¹ kg⁻¹ in healthy adults. Although coadministration with food results in a delayed absorption [the time to reach C_max (t_max) 2.1–2.3 h], the decreased extent of absorption (by approximately 8–10%) is not of clinical significance [11].

The pharmacokinetic, efficacy and safety profiles of levetiracetam have been well established in White populations but have never been studied in Chinese subjects. The present study was designed to (i) investigate the pharmacokinetics of levetiracetam and assess dose proportionality between the 500-mg and 1500-mg single dose in healthy male Chinese volunteers; (ii) compare the results with published data obtained in Whites; (iii) gain information on the safety and tolerability profile of levetiracetam in Chinese subjects.

Methods

Study populations

Twenty-six healthy male Chinese subjects between 20 and 36 years of age were included following regular medical assessments, including laboratory safety screens. Subjects were nonsmokers or able to stop smoking throughout the study period. Subjects testing positive for HIV, hepatitis B surface antigen, hepatitis C virus or drugs of abuse (including alcohol) were excluded. Subjects with a history of frequent and severe headache were also excluded.

All subjects provided written informed consent. The study protocol was approved by Peking Union Medical College Hospital (PUMC Hospital) Ethics Committee, Beijing, China.

Study design

This was a randomized, single-centre, single-dose, two-way crossover study of 500-mg and 1500-mg levetiracetamin tablet(s) in healthy, adult male Chinese subjects after an overnight fast. In each study period, the subjects received 1 × 500 mg or 3 × 500 mg film-coated tablets of levetiracetam. These two treatments were separated by a 7-day wash-out period. All subjects were not allowed to take food until 4 h postdose on the dosing days. Blood samples for determination of levetiracetam plasma concentrations were taken predose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, 12, 24 and 36 h postdose.

Safety was evaluated by monitoring adverse events, vital signs, physical examinations, clinical laboratory tests and electrocardiograms (ECGs).

Analytic assays

Plasma samples were analysed by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method,which was fully validated according to the Standard Operation Procedure of PUMC Hospital and Good Laboratory Practice guidelines. The calibration curve ranged from 0.10 to 50 µg ml⁻¹. Plasma samples (100 µl) were mixed with 50 µl of internal standard solution (ucb 17025, 5 µg ml⁻¹) and 350 µl acetonitrile. After centrifugation, 100 µl of the supernatant was diluted with 300 µl of water. Following plasma sample preparation, injection (20 µl) was made onto an Alltech C18 column (4.6 × 100 mm, 3 µm) using 60% 2 mm ammonia acetate, 30% acetonitrile, 30% 0.1% formic acid as mobile phase.

Pharmacokinetic analysis

Pharmacokinetic parameters resulting from the plasma concentrations of levetiracetam were calculated with WinNonlin (Pharsight 4.0.1; SCI software, Cary, NC, USA) by noncompartmental methods. The C_max and t_max were obtained directly from the concentration–time data. AUC_0–t was calculated using the trapezoidal rule and extrapolated to infinite time for AUC_0–∞. The CL/F, V_z/F and terminal phase t_1/2 were also calculated.

Statistical methods

The dose proportionality of between 500 mg and 1500 mg was assessed. The logarithmically (ln) transformed parameters (C_max, AUC_0–t and AUC_0–∞ adjusted for dose) were evaluated according to a univariate model of analysis of variance, adapted to crossover experimental designs. The 90% confidence intervals (CI) of the adjusted 1500-mg dose/500-mg dose geometric mean ratio were calculated. Bioequivalence of the reference (500 mg) and test (1500 mg) doses was concluded if these limits for AUC_0–t, AUC_0–∞ fell within 0.80–1.25 and for C_max within 0.70–1.43.

The pharmacokinetics of levetiracetam in Chinese subjects were compared with those of levetiracetam in matched White subjects obtained in previous studies using similar dosages. For each dose, the logarithmically (ln) transformed parameters (C_max, AUC_0–t and AUC_0–∞ with and without body weight adjustment) were evaluated according to a univariate model of analysis of variance, adapted to parallel group experimental designs. The 90% CI of the Chinese group/White group geometric mean ratio were calculated. Lack of difference between pharmacokinetics of levetiracetam in Chinese and historical White data was concluded if these intervals fell within limits of 0.80–1.25 for either the original or body weight-adjusted AUC_0–∞, AUC_0–t, and within 0.70–1.43 for C_max. The UNIanova procedure in SPSS (Version 11.0) software was used for this analysis (SPSS Inc., Chicago, IL, USA).

Results

Pharmacokinetics

Twenty-six healthy male Chinese subjects were included. The demographic details were as follows (mean ± SD): age was 24.0 ± 4.3 years, weight 64.3 ± 6.8 kg, height 1.72 ± 0.06 m and body mass index 21.74 ± 1.69 kg m⁻².

Figure 1 shows the mean concentration–time profile of levetiracetam following single oral doses of 500 mg and 1500 mg. Levetiracetam was rapidly absorbed after administration. C_max was reached within 1 h after dosing. The pharmacokinetic parameters are shown in Table 1. C_max and AUCs were proportional to the administrated dose, since the 90% CIs of 1500 mg/500 mg for dose-normalized C_max, AUC_0–t and AUC_0–∞ were within the established acceptable ranges.

Figure 1.

Plasma concentration (arithmetic mean ± SD)–time curve of levetiracetam following a single administration of a 500-mg (•) oral tablet or a 1500-mg (○) oral tablet (3 × 500-mg tablets) in 26 Chinese male healthy subjects. Upper panel: arithmetic scale; lower panel: logarithmic scale

Table 1.

Pharmacokinetic parameters of levetiracetam after a single-dose administration of a 500-mg oral tablet or a 1500-mg oral tablet (3 × 500-mg tablets) in 26 healthy male Chinese subjects

Parameters	Levetiracetam 500-mg tablet*	Levetiracetam 1500-mg tablet*	CV (%)†	Geometric mean ratio, % (90% CI)‡(dose adjusted)
Cmax (µg ml−1)	13.6 ± 3.2	47.1 ± 12.1	23.2	114.8 (104.0, 125.7)
tmax (h)	0.5 (0.25–2.0)	0.5 (0.25–1.25)	NA	NA
AUC0–t (µg h−1 ml−1)	105.7 ± 13.3	329.0 ± 47.9	6.6	103.6 (100.5, 106.7)
AUC0–∞ (µg h−1 ml−1)	109.3 ± 14.1	340.4 ± 50.6	6.6	103.6 (100.5, 106.7)
t1/2 (h)	7.3 ± 0.8	7.3 ± 0.7	NA	NA
CL/F (l h−1)	4.7 ± 0.6	4.5 ± 0.6	NA	NA
Vz/F (l)	48.5 ± 6.8	47.4 ± 7.0	NA	NA

^*Values are arithmetic mean ± SD except for t_max, where values are median (range).

^†Intra-individual CV (%).

^‡Point estimate and 90% CI for the adjusted 1500-mg/500-mg geometric least squares mean ratio (%), derived from anova for continuous parameters.

NA, Not applicable.

The pharmacokinetics of levetiracetam in 26 Chinese and in 19 matched White subjects were evaluated by a bioequivalence approach. The geometric mean ratios between the two populations were as follows: for the 500-mg group, the geometric mean ratios (90% CIs) of C_max, AUC_0–t, AUC_0–∞ and weight-adjusted C_max, AUC_0–t, AUC_0–∞ were 96.1% (84.5, 109.3), 102.8% (95.8, 110.4), 92.1% (85.4, 99.3) and 96.1% (84.4, 109.5), 102.8% (96.2, 109.9), 92.1% (86.1, 98.4), respectively; for the 1500-mg group, the geometric mean ratios (90% CIs) were 120.6% (105.9, 137.4), 89.5% (83.2, 96.4), 89.5% (83.1, 96.4) and 120.6% (105.8, 137.4), 89.5% (84.0, 95.5), 89.5% (83.7, 95.7), respectively. The comparison demonstrated similar pharmacokinetic data between the two populations, since the 90% CIs of geometric means ratios for either the original or weight-adjusted parameters were entirely within reference boundaries of 0.80–1.25 for AUC_0–∞, AUC_0–t and within 0.70–1.43 for C_max.

Adverse events

Adverse events observed in the study included somnolence, dizziness and nausea. All adverse events were considered treatment related, mild or moderate in severity, and transient and resolved without treatment. The incidence and profile of adverse events between the 500-mg and 1500-mg groups were comparable and not dose-related.

Discussion

This study showed that the pharmacokinetic data of levetiracetam in healthy adult male Chinese subjects were similar to historical data in White subjects. The t_max of levetiracetam in Chinese subjects was 0.5 h, compared with the within 1 h found in White subjects. The t_1/2, CL/F equated for weight and V_z/F equated for weight were comparable in Chinese and White subjects (t_1/2 −7.2 h, CL/F ∼1.43 ml min⁻¹ kg⁻¹ and V_z/F ∼0.5–0.8 l kg⁻¹). Because different dietary conditions in this comparison with historical data could have affected the absorption rate, while the clinical efficacy of levetiracetam was likely to be related to absorption and overall exposure rather than to absorption rate and peak exposure, a broader range of acceptance (0.70–1.43) was selected for C_max. The results of this study indicated that both C_max and AUCs could be considered to be dose proportional over the tested dose range of 500–1500 mg in Chinese subjects, which is in line with previously published results on levetiracetam linear pharmacokinetics (range 500–5000 mg) in White subjects [11].