文章标题：

1，采用名词词组形式；
2，第一个单词的首字母大写；
Epilepsy Research 64 (2005) 1–11
3，分为主标题和副标题，冒号
前面为主标题，后面为副标
题。
Effect of levetiracetam on the pharmacokinetics of adjunctive
antiepileptic drugs: A pooled analysis of data from
randomized clinical trials
该篇文章的结构为典型的温哥华模式，即“IMRAD”模式，分为
Barry E. Gidal a,∗ , Eugène Baltès b , Christian Otoul c , Emilio Perucca d
简介、方法、结果、讨论四个部分；同时增加了结论部分。
a School of Pharmacy & Department of Neurology, University of Wisconsin, 777 Highland Ave., Madison, WI 53705, USA
b Department of Drug Metabolism and Pharmacokinetics, UCB S.A. Pharma, Braine-L’Alleud, Belgium 药代动力学对辅助抗
c Department of Biostatistics, UCB S.A. Pharma, Braine-L’Alleud, Belgium
简要介绍左乙拉西坦的用量及对照组的
d Laboratories for Diagnostics and Applied Biological Research and Neuropharmacology Unit,
癫痫药物左乙拉西坦
安慰剂等，同时简要说明统计方法的应
Institute of Neurology, IRCCS C. Mondino Foundation, Pavia, Italy 的影响：汇集分析数
用（90%的置信区间）
Received 14 December 2004; accepted 19 January 2005
据随机临床试验
Available online 8 April 2005

[levt'restæm]
Abstract 本项研究意在确定常用抗癫痫药物对其
他稳态血清浓度的影响
The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other
commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy
with levetiracetam (1000–4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving
stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and
90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative
to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin,
valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of
the geometric mean drug concentrations ratio was included within the 80–125% bioequivalence range. Serum concentrations of
these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used.
For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam,
but the number of observations was too small for the limits of the confidence interval to fall within the 80–125% range. Thus,
adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered
carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for
adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient’s therapeutic
regimen. 摘要部分基本上涵盖了文章
© 2005 Elsevier B.V. All rights reserved.
的研究目的、方法、结果、 在90%的可信区间内，左乙拉西坦
结论等。最终我们的除了左
Keywords: Levetiracetam; 不会影响比如拉莫三嗪、加巴喷丁
Antiepileptic drugs; Pharmacokinetics; Serum concentrations; Drug interactions

乙拉西坦在90%可信区间内 等的药物浓度。但观测的数量太
可以不影响其他药物的使 少，在80至125%范围内的置信区
∗ Corresponding author. Tel.: +1 608 262 3280; fax: +1 608 265 5421.
用。
E-mail address: BEGidal@pharmacy.wisc.edu (B.E. Gidal). 间的限制。

0920-1211/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.eplepsyres.2005.01.005
 回顾历史，凸显研究目的：“左乙拉
西坦会影响血清药物浓度吗？”
漏斗模式(funnel m odel)
2 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11
1. Introduction
Levetiracetam (Keppra® ) is used worldwide as
adjunctive treatment for partial epilepsy. In pre-
clinical models, levetiracetam exhibits a unique profile
characterized by broad-spectrum seizure protection
and a low induction of adverse effects (Klitgaard
et al., 1998). Its exact mechanism of action remains
目前行业内研究 to be ascertained, but it appears to differ from that of
现状，归类为历 other antiepileptic drugs (AEDs) and to be mediated
by a selective interaction with synaptic vesicle protein
史回顾。 SVA2 (Lynch et al., 2004). A series of multicenter,
randomized, controlled trials established the safety
and efficacy of levetiracetam in patients with re-
明确左乙拉西坦 fractory partial seizures, with or without secondary
的全球应用价值 generalization (Cereghino et al., 2000; Shorvon et al.,
以及其广谱的抗 2000; Ben-Menachem et al., 2000; Betts et al., 2000).
In these studies, adjunctive therapy with levetiracetam
癫痫作用。突出
at daily doses of 1000–4000 mg significantly reduced
其分子生物学上 seizure frequency relative to placebo.
的作用机制 Levetiracetam is rapidly and almost completely ab-
（ selective sorbed from the gastrointestinal tract, reaching peak
interaction with serum concentrations by approximately 1 h (Patsalos,
2000; Radtke, 2001). Drug concentrations increase
synaptic vesicle linearly with increasing dosage over the clinically
protein used dose range, and the extent of absorption is
SVA2，突触囊泡 not affected by food. Steady-state concentrations are
蛋白选择性的相 achieved within 48 h of starting therapy. The elimina-
互作用）。 tion half-life is in the order of 6–8 h, but longer values
are observed in the elderly and in patients with renal
作为辅助治疗， impairment (Patsalos, 2000). About 70% of an orally
副作用小。 administered levetiracetam dose is excreted unchanged
in urine, and about 25% is hydrolyzed to an inactive
acidic metabolite (Strolin Benedetti et al., 2003). Leve-
tiracetam does not bind significantly to plasma proteins
and does not affect the activity of various cytochrome
P450 isoenzymes, epoxide hydrolase, or enzymes re-
sponsible for glucuronide conjugation (Patsalos, 2000;
Nicolas et al., 1999).
On the basis of these pharmacokinetic properties,
levetiracetam is not expected to interact with concomi-
tantly administered AEDs, a prediction that is line
with findings from clinical studies performed to date.
To more comprehensively evaluate the potential for
pharmacokinetic interactions between levetiracetam
and other AEDs, pooled analyses have been conducted
using data collected during the phase III clinical
development program. In a first set of such analyses,
左乙拉西坦几乎完
全从肠道吸收，但
不受食物影响，这
具体规范研究方法
是天然的优势。半
衰期6-8小时，老人
及肾病患者有所出
入。2/3在尿液排
泄，其余化作酸性
代谢物。
the steady-state pharmacokinetics of levetiracetam
were shown to be independent of dose (within the
1000–4000 mg/day range) and not affected to any
major extent by other AEDs (Perucca et al., 2003), sug-
gesting that the dose of levetiracetam does not need to
be adjusted according to the type of AED comedication.
The present pooled analysis was designed to ascertain
whether levetiracetam affects the steady-state serum
concentration of concomitantly administered AEDs.
漏斗模式之“方法”：1.研
2. Methods 究设计和抽样方案；2.数据
分析
2.1. Study design and sampling schedule
The analysis was conducted on data from four phase
III controlled trials, in which 1023 adults with refrac-
tory partial seizures were randomly assigned to adjunc-
tive therapy with levetiracetam or placebo (Table 1).
These studies were of similar design: each included
a prospective baseline period of 4–12 weeks, during
which patients received a stable background regimen
with one to three standard AEDs, followed by a double-
blind treatment period during which either levetirac-
etam (1000, 2000, 3000, or 4000 mg/day in two equally
divided daily doses) or placebo were added on (Perucca
et al., 2003). The adjunctive therapy period included a
2–6-week titration phase during which the levetirac-
etam dose was increased gradually, and a 12–24-week
maintenance phase. Study N052 (Betts et al., 2000) did
not include a titration phase and patients entered di-
rectly the maintenance phase. According to the study
protocol, AED comedication had to remain unchanged
throughout the trial.
Eight AEDs, representing the most commonly co-
administered agents in these studies, were selected
for evaluation: carbamazepine, phenytoin, valproic
acid, lamotrigine, gabapentin, phenobarbital, primi-
done, and vigabatrin. Serum concentrations of these
AEDs were determined at regular intervals during the
prospective baseline and the adjunctive therapy pe-
riod, including three study visits during the mainte-
nance phase of levetiracetam or placebo treatment. In
the case of primidone, the statistical analysis was also
performed on metabolically derived phenobarbital. Al-
though for practical reasons, times of sampling could
not be standardized, the distribution of sampling times
for all AEDs was comparable at each study visit.
常见的抗癫痫药物：卡马
西平、苯妥英钠、丙戊酸
酸、拉莫三嗪、加巴喷
丁、苯巴比妥、扑米酮，
与氨己烯酸
 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11 3
表示转折，由已
For each patient, the reference (baseline) AED con- 知信息转到未知
Duration of maintenance

centration was calculated as the arithmetic mean of all 信息

determinations made during the baseline period when
period (weeks)

the patient was on a constant AED dose. However, a

few patients had a small adjustment of their dose at
entry into the study. Baseline data during this adjust-
12–24

ment period were not used in the computation of the

12

24

14

12

mean baseline value if the difference between the blood

对照组踢出特殊情 sampling date and the date of the last dose adjustment
Patients (n) with 1

况：丙戊酸钠
or >1 other AEDs

1 (313), >1 (359)

was less than 10 days. For all patients except one on

1 (23), >1 (83)
1 (19), >1 (87)
1 (10), >1 (32)

1 (35), >1 (63)

1 (36), >1 (65)

（10d）、苯妥英钠
1 (9), >1 (29)

monotherapy valproic acid (10 days) and two on pheny-

的应用（12、13 toin (12 and 13 days), at least 14 days at a constant
1 (181)

天） AED dose was observed for each baseline drug con-

centration used in the mean value. To eliminate the
如果没有血清AED confounding effects of dose changes, drug concentra- 消除剂量变化的
Other AEDs

浓度测量可在基线 tion measurements obtained when a change had oc- 混杂效应，实验

allowed
Up to 2

Up to 3

Up to 2

Up to 1

curred in the concomitant AED were excluded from the

或在维持期，病人 evaluation.
更加合理
被认为非评估。患 Levetiracetam and placebo-treated patients were
者的药物剂量是在 included in the interaction assessment evaluation if
366/306
Gender
(M/F)

治疗期间被排除在
51/55
51/55
29/13
20/18
62/36
66/35
87/94

they received a constant dose of a given AED dur-

外从分析。患者接 ing the baseline period and throughout the treat- 三次评估中的每
ment period. If no serum AED concentration mea-
受多个随之而来的 一个相以及在所
mean ± S.D. (range)

surements were available either at baseline or dur-

AED包括在人群每 有访问相结合与
36 ± 10 (16–68)
37 ± 12 (14–65)
39 ± 13 (18–67)
40 ± 12 (23–66)
38 ± 11 (16–70)
38 ± 11 (16–66)
37 ± 12 (17–70)
37 ± 11 (14–70)

ing the maintenance period, the patient was consid-

种药物，提供他们 ered non-evaluable. Patients whose drug dose was 平均基线浓度比
Age (years),

满意的资格标准。 changed during the treatment period were excluded 较。反复对比实

from the analysis. Patients receiving more than one 验，使实验更趋
concomitant AED were included in the populations for
合理
Characteristics of the phase III studies included in the pooled analysis

each drug, providing they satisfied the above eligibility

Levetiracetam maintenance

criteria.
In order to assess the effect of levetiracetam on the
serum concentrations of each concomitantly adminis-
tered AED, serum AED concentrations measured at
Reprinted with permission from Shorvon et al. (2003).
dose (mg/day)

each of the three evaluation visits during the main-

1000–4000

tenance phase as well as at all visits combined were

抗癫痫药物
1000
2000
2000
4000
1000
3000
3000

compared with the average baseline concentration.

统计分析 2.2. Statistical analysis

d Ben-Menachem et al. (2000).
Study (n of levetiracetam-treated

统计方法：重复测 All evaluable patients were included in the statis-

c Cereghino et al. (2000).

量分析和协方差
a Shorvon et al. (2000).
All four studies (n = 672)

tical analysis. Serum AED concentrations were log-

AED, antiepileptic drug.
Study N138 (n = 181)d
Study N051 (n = 212)a

Study N132 (n = 199)c

b Betts et al. (2000).

（SAS PROC）
Study N052 (n = 80)b

transformed, and then a repeated measure analysis

of covariance (SAS PROC MIXED) was performed
(Littell et al., 1996). A two one-sided t-test approach 统计方法二：单
was used (Schuirmann’s test), which is the proce- 侧t检验
patients)
Table 1

dure used for bioequivalence assessment (Schuirmann, （Schuirmann）

1987). This test is a combination of two tests (one
统计分析方法
4 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11
for the lower bound: 80%; one for the upper bound:
125%) with a one-sided region of rejection, and it is a
procedure used for testing lack of interaction
(Steinijans et al., 1991).
For each selected AED, the ratio of the geometric
means of the drug concentration at the evaluation visit
relative to baseline and its 90% confidence intervals
were determined. A clinically significant AED con-
centration change was excluded if both limits of 90%
confidence intervals were within the 80–125% interval,
which corresponds with the generally accepted interval
in bioequivalence studies. 苯巴比妥
For each AED, the pooled data set was also
evaluated using analysis of covariance to determine
if levetiracetam produced a time-dependent effect on
假设基础选定的 the concentration of a concomitant AED. Analyses of
模型进行了验证 individual studies were also performed for proof of
调查残差的正态 consistency. To evaluate the change from baseline over
time, the model included terms for log-transformed
性（直方图，盒 average baseline value, evaluation visit, levetiracetam
样地，普通的概 dose (including a dose of 0 for placebo), and the eval-
率图，和正态性 uation visit by dose interaction. A term for study effect实验对比数
检验利用SAS was not included in the model because of the con-据分析
PROC单变量统 founding effect of differences in levetiracetam dosages
across studies. An unstructured covariance matrix was
计）以及残差与 used to model the dependency between repeated factors
预测值的图 (i.e., evaluation visit within subject). The assumptions
underlying the selected models were verified by
investigating the normality of residuals (histograms,
box plots, normal probability plots, and normality test
statistics using SAS PROC UNIVARIATE) as well as
plots of residuals versus predicted values.
漏斗模式之三“结
论”：1.对病人的影
3. Results
响；2.血药浓度
3.1. Evaluable patient population
Details of the 672 patients assigned to levetiracetam passed unity (with the single exception of phenytoin),
in the four studies are summarized in Table 1. Of this
group, 313 (46.6%) received one concomitant AED
and 359 (53.4%) received more than one AED. In both
the levetiracetam and placebo groups, carbamazepine
was the most common comedication, with 83.4% of
carbamazepine-treated patients in the combined leve-
大数据时 tiracetam group and 88.3% of those in the combined
代，672例分为 placebo group being evaluable (Table 2). For the re-
四组 maining AEDs other than vigabatrin, the percentage of
卡马西平
表3，左乙拉西坦或
安慰剂治疗期间血
清药物浓度
目前国际公认的90%的可信
区间，生物等效性研究
氨己烯酸
evaluable patients ranged from 74.6 to 87.7% in the lev-
etiracetam group and from 73.2 to 85.5% in the placebo
group. The majority of vigabatrin-treated patients, on
the other hand, were non-evaluable because serum vi-
gabatrin concentrations were frequently unavailable in
patients taking this drug. 加巴喷丁
Only a small proportion of patients had changes in
dosage of comedication during the study (Table 2). The
proportion of patients with comedication dose changes
tended to be higher in the combined placebo group than 苯妥
in the combined levetiracetam group for valproic acid 英
(11.8% versus 4.3%), gabapentin (13.8% versus 7.7%),
and phenobarbital (14.6% versus 8.5%), whereas the
reverse was true for phenytoin (7.9% versus 13.8%). In
particular, a decrease in phenytoin dosage was some-
what more frequent in the levetiracetam group: of the
15 patients with a decrease in phenytoin dose during 苯妥
levetiracetam treatment, 9 had a slight dose decrease, 3 英钠
had a decrease followed by an increase, and 3 returned
to their initial dose.
3.2. Influence of levetiracetam on serum
concentrations of concomitant AEDs 丙戊酸
Mean steady-state serum concentrations of co-
administered AEDs during the baseline period and dur-
ing the adjunctive levetiracetam or placebo period are
shown in Table 3.
For all AEDs, 90% confidence intervals for geomet-
ric means ratios between levetiracetam treatment and
baseline periods encompassed unity, except for carba-
mazepine and valproic acid, for which the upper limits
of the ratio (0.99 and 0.97, respectively) were just
below unity. For all AEDs other than vigabatrin, 90%
confidence intervals were well within the 80–125%
boundary (Fig. 1). In the combined placebo groups,
90% confidence limits for geometric means ratios
between treatment and baseline periods also encom-
and 90% confidence intervals were equally within
the 80–125% boundary for all AEDs other than
vigabatrin. For vigabatrin, geometric means ratios
between treatment and baseline periods (0.875 for
the levetiracetam group and 1.020 for the placebo
group) did not suggest any significant change in drug
concentration during adjunctive treatment, but due to
the small number of observations, 90% confidence
limits exceeded the 80–125% interval.
基线期
数据分析
 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11 5

Table 2
Number (%) of patients with dose changes and/or missing dataa
AED Patient classification Placebo n (%) Levetiracetam n (%)
Carbamazepine Evaluable 212 (88.3) 368 (83.4)
Dose changeb 15 (6.2) 33 (7.4)
Decrease 14 (5.8) 25 (5.6)
Increase 1 (0.4) 8 (1.8)
Missing data 13 (5. 4) 40 (9.0)
Total 240 441
Phenytoin Evaluable 65 (85.5) 109 (75.2)
Dose changeb 6 (7.9) 20 (13.8)
Decrease 4 (5.3) 16 (11.0)
Increase 2 (2.6) 3 (2.1)
Discontinuationc 0 1 (0.7)
Missing data 5 (6.6) 16 (11.0)
Total 76 145
Valproic acid Evaluable 56 (82.4) 118 (84.9)
Dose changeb 8 (11.8) 6 (4.3)
Decrease 4 (5.9) 4 (2.9)
Increase 4 (5.9) 2 (1.4)
Missing data 4 (5.9) 15 (10.8)
Total 68 139
Lamotrigine Evaluable 25 (78.1) 48 (78.7)
Dose changeb 3 (9.4) 4 (6.6)
Decrease 3 (9.4) 3 (4.9)
Discontinuation 0 1 (1.7)
Missing data 4 (12.5) 9 (14.8)
Total 32 61
Gabapentin Evaluable 22 (75.9) 57 (87.7)
Dose changeb 4 (13.8) 5 (7.7)
Decrease 0 4 (6.2)
Increase 4 (13.8) 0
Discontinuation 0 1 (1.5)
Missing data 3 (10.3) 3 (4.6)
Total 29 65
Phenobarbital Evaluable 30 (73.2) 44 (74.6)
Dose changeb 6 (14.6) 5 (8.5)
Decrease 1 (2.4) 4 (6.8)
Increase 3 (7.3) 1 (1.7)
Discontinuationc 2 (4.9) 0
Missing data 5 (12.2) 10 (16.9)
Total 41 59
Primidone Evaluable 15 (83.3) 20 (76.9)
Dose change (decrease) 0 (0) 1 (3.8)
Missing data 3 (16.7) 5 (19.2)
Total 18 26
Vigabatrin Evaluable 9 (29.0) 12 (24.0)
Dose change (decrease) 1 (3.2) 0 (0)
Missing data 21 (67.7) 38 (76.0)
Total 31 50
AED, antiepileptic drug.
a Missing data refers to patients with no available AED concentrations during baseline and/or evaluation visits.
b Some patients who experienced a decrease or increase in dose returned to their initial dose.
c After use of <4 days (complete discontinuation to meet inclusion criteria on the number of AEDs permitted).
6 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11

Table 3
Mean serum concentrations of antiepileptic drugs (arithmetic means) at baseline and during adjunctive treatment with levetiracetam or placebo,
and ratios of geometric means (adjunctive treatment over baseline) with corresponding 90% confidence intervals (CI)
Drug N Mean serum concentrations (␮g/mL) Ratio of geometric
means (90% CI)
Baseline Treatment
With levetiracetam
Carbamazepine 368 8.71 8.62 0.978 (0.963–0.993)
Phenytoin 109 13.99 14.36 0.990 (0.942–1.041)
Valproic acid 118 75.2 71.6 0.941 (0.909–0.974)
Lamotrigine 48 6.15 6.03 0.979 (0.922–1.039)
Gabapentin 57 6.63 6.71 0.979 (0.914–1.049)
Phenobarbital 44 26.5 27.0 1.014 (0.962–1.069)
Primidone 20 11.15 10.66 0.954 (0.888–1.024)
Vigabatrin 12 13.59 12.49 0.875 (0.673–1.137)a
With placebo
Carbamazepine 212 8.49 8.53 0.989 (0.969–1.010)
Phenytoin 65 14.31 13.69 0.887 (0.831–0.947)
Valproic acid 56 68.1 69.0 0.974 (0.925–1.025)
Lamotrigine 25 5.97 6.41 1.039 (0.956–1.129)
Gabapentin 22 6.17 6.95 0.987 (0.882–1.105)
Phenobarbital 30 24.4 26.5 1.064 (0.997–1.136)
Primidone 15 8.11 9.27 1.058 (0.970–1.155)
Vigabatrin 9 11.99 12.41 1.020 (0.742–1.402)a
a 90% CI outside the 0.80–1.25 range.

Fig. 1. Ratio of the geometric mean serum concentrations of concomitant antiepileptic drugs (AEDs) during adjunctive levetiracetam (LEV)
therapy (all measured values) compared with baseline. Bars represent 90% confidence intervals. CBZ, carbamazepine; GBP, gabapentin; LTG,
lamotrigine; PB, phenobarbital; PB(PRM), metabolically derived phenobarbital; PHT, phenytoin; PRM, primidone; VGB, vigabatrin; VPA,
valproic acid.
 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11 7

Table 4
Ratios of the geometric mean serum concentrations (and 90% confidence intervals (CI)) for concomitantly administered antiepileptic drugs
(AEDs) at each of the three evaluation visits during adjunctive therapy with levetiracetam or placebo compared with baseline
AED and evaluation visita Placebo Levetiracetam
Carbamazepine
Visit 1 1.006 (0.981–1.031) 0.977 (0.959–0.996)
Visit 2 0.986 (0.961–1.018) 0.980 (0.959–1.002)
Visit 3 0.974 (0.947–1.001) 0.976 (0.955–0.996)
Phenytoin
Visit 1 0.874 (0.810–0.944) 0.966 (0.912–1.024)
Visit 2 0.870 (0.798–0.947)b 0.992 (0.929–1.060)
Visit 3 0.918 (0.846–0.995) 1.012 (0.950–1.078)
Valproic acid
Visit 1 0.949 (0.879–1.024) 0.923 (0.876–0.972)
Visit 2 0.998 (0.927–1.075) 0.922 (0.877–0.970)
Visit 3 0.974 (0.915–1.037) 0.979 (0.939–1.021)
Lamotrigine
Visit 1 1.031 (0.927–1.147) 0.977 (0.904–1.057)
Visit 2 1.063 (0.972–1.164) 0.985 (0.923–1.051)
Visit 3 1.023 (0.929–1.126) 0.975 (0.910–1.045)
Gabapentin
Visit 1 1.080 (0.933–1.250) 0.968 (0.886–1.057)
Visit 2 0.994 (0.869–1.137) 1.023 (0.942–1.110)
Visit 3 0.896 (0.778–1.033)b 0.949 (0.869–1.036)
Phenobarbital
Visit 1 1.026 (0.947–1.110) 1.029 (0.966–1.096)
Visit 2 1.047 (0.967–1.134) 1.002 (0.940–1.069)
Visit 3 1.121 (1.024–1.227) 1.011 (0.941–1.085)
Primidone
Visit 1 1.048 (0.939–1.170) 0.968 (0.882–1.063)
Visit 2 1.086 (0.962–1.226) 0.907(0.822–1.001)
Visit 3 1.042 (0.952–1.140) 0.988 (0.925–1.054)
a Vigabatrin not assessed due to few observations at some evaluation visits.
b 90% CI outside the 0.80–1.25 range.

Data from the four combined phase III studies
showed no alteration in the serum concentrations
of concomitant AEDs over time or in relation with
the levetiracetam dose. At each of the three evalu-
ation visits during adjunctive maintenance therapy,
the 90% confidence intervals for geometric means
ratios between levetiracetam treatment and baseline
periods for carbamazepine, phenytoin, valproic acid,
lamotrigine, gabapentin, phenobarbital, and primidone
were all within the 80–125% boundaries (Table 4).
Similar results were found in the combined placebo
group, except for phenytoin at the second evalu-
ation visit and gabapentin at the third evaluation
visit, when the lower limits of confidence interval
拉莫三嗪 扑米酮
were just below the 80% boundary (79.8 and 77.8%,
respectively).
For all the dose levels of levetiracetam where the
number of subjects included in the statistical anal-
ysis was at least 15, 90% confidence intervals for
geometric means ratios between treatment and base-
line periods for carbamazepine, phenytoin, valproic
acid, gabapentin, phenobarbital, and primidone were
within the 80–125% boundaries (Table 5). For the 16
lamotrigine-treated patients assigned to receive leve-
tiracetam 2000 mg/day, the lower limit of the 90% con-
fidence interval for lamotrigine geometric means ratio
(adjunctive levetiracetam therapy versus baseline) was
just below 80% (78.5%). This effect was not seen in pa-
类似的结果被发现
在联合安慰剂组，
除在第二评价苯妥
英钠在第三个评价
访问和加巴喷丁访
问时，下限的置信
区间下的77.8%个边
界（79.8和80%，分
别）
 8 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11

Table 5
Ratio of the geometric mean serum concentrations (and 90% confidence intervals (CI)) of concomitantly administered antiepileptic drugs (AEDs)
during adjunctive therapy with different dosages of levetiracetam compared with baseline
Concomitant AED Dosage of levetiracetam (mg/day)

1000 2000 3000 4000

Carbamazepine
Subjects, n 112 81 158 17
Ratio 0.979 1.002 0.963 0.990
90% CI 0.952–1.007 0.969–1.036 0.941–0.987 0.921–1.065
Phenytoin
Subjects, n 47 21 32 9
Ratio 0.994 1.000 0.972 ND
90% CI 0.921–1.074 0.891–1.122 0.886–1.066
Valproic acid
Subjects, n 42 29 42 5
Ratio 0.969 0.944 0.935 ND
90% CI 0.915–1.027 0.878–1.014 0.881–0.991
Lamotrigine
Subjects, n 15 16 15 2
Ratio 1.007 0.869 1.048 ND
90% CI 0.907–1.118 0.785–0.962a 0.938–1.170
Gabapentin
Subjects, n 30 4 21 2
Ratio 0.980 ND 0.922 ND
90% CI 0.892–1.078 0.822–1.033
Phenobarbital
Subjects, n 17 16 8 3
Ratio 0.995 1.022 ND ND
90% CI 0.913–1.085 0.934–1.118
Primidone
Subjects, n 6 4 8 2
Ratio ND ND ND ND
Vigabatrin
Subjects, n 1 7 2 2
Ratio ND ND ND ND

ND, not determined due to insufficient sample size (< 15 subjects).

a 90% CI outside the 0.80–1.25 range.
讨论部分
tients treated with either 1000 or 3000 mg/day of leve- 4. Discussion 点题：表明目的
tiracetam, however. Indeed, in these treatment groups,
the limits for the lamotrigine geometric means ratios The present analysis was designed to determine
were within the 80–125% limits. whether levetiracetam given as adjunctive therapy
For primidone treated patients, the possibility of affects the steady-state serum concentrations of
an interaction was also assessed for the serum con- concomitantly administered AEDs. The results
centrations of the metabolite phenobarbital. At all demonstrate that levetiracetam neither significantly
分析表5，90%的 levetiracetam and placebo treatment visits, geometric increases nor decreases the serum concentrations of
置信区间为治疗 means ratios between treatment and baseline periods carbamazepine, phenytoin, valproic acid, lamotrigine,
和基线之间的几 for metabolically derived phenobarbital were within gabapentin, phenobarbital, or primidone (including
何均值比期丙戊 the 80–125% boundaries (Table 6). phenobarbital metabolically derived from primidone)
酸钠卡马西平，
苯妥英，酸和苯
巴比妥，加巴喷
分析表6，即扑米
丁
酮的具体表达
 B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11
Table 6
Serum concentrations of phenobarbital in patients taking primidone (arithmetic means with S.D.) at baseline and during adjunctive treatment
with levetiracetam or placebo, and ratios of geometric means (adjunctive treatment over baseline) with corresponding 90% confidence intervals
(CI)
Study visit Placebo (N = 10)
Mean (S.D.) ␮g/mL Ratio of geometric
means (90% CI)
Baseline 19.05 (7.63) – 26.86 (9.01)
Visit 1 19.70 (7.81) 0.979 (0.901–1.064)
Visit 2 17.97 (6.34) 0.927 (0.859–1.000)
Visit 3 17.53 (9.08)a 0.963 (0.869–1.068)
All visits 18.50 (7.41) 0.956 (0.896-1.020)
a N = 7.
in patients receiving stable dosages of these AEDs.
While the confidence limits for mean changes in the
serum concentrations of carbamazepine and valproic
acid after levetiracetam therapy did not encompass
unity, the magnitude of these changes (2 and 6%,
respectively) was clearly of no clinical relevance.
More importantly, for each AED other than vigabatrin,
the 90% confidence intervals for the ratio of geometric
mean serum concentrations during levetiracetam ther-
apy compared with baseline were within the 80–125%
range, thereby excluding any clinically important
interaction. This conclusion is further supported by the
finding that the serum concentrations of these drugs
did not change over time after starting levetiracetam,
nor was it modified in relation to levetiracetam over
the 1000–3000 mg/day dosage range. At the highest
dose of 4000 mg/day, levetiracetam did not influence
the serum concentration of carbamazepine, whereas
the number of subjects treated with other AEDs at
this dosage level was too small for a meaningful
assessment.
As previously discussed, concentration mea-
surements taken when the dosage of comedication
was modified were excluded from the evaluation.
Theoretically, this could introduce a selection bias
through potential exclusion of patients who had
shown an interaction sufficiently marked to require an
adjustment in comedication dosage. This possibility,
however, can be ruled out confidently for a number
of reasons: (1) the number of patients who had a
change in dosage of evaluable comedications during
levetiracetam treatment was very small (from 4% with
primidone and valproic acid to 14% with phenytoin);
(2) the proportion of patients in whom dosage was
此段主要说明药物 本文缺陷，已被进
左乙拉西坦与其他 一步提出进展
药物比较，用数据
发现：左乙拉西坦
不会影响血清药物
浓度
9
Levetiracetam (N = 17)
Mean (S.D.), ␮g/Ml Ratio of geometric
means (90% CI)
–
27.59 (7.96) 1.090 (1.024–1.160)
26.89 (7.18) 1.073 (1.013–1.136)
26.40 (6.01) 1.067 (1.001–1.137)
26.96 (6.97) 1.077 (1.028–1.127)
modified in the levetiracetam-treated group was
similar to or even lower than that observed in the
placebo group (with the exception of phenytoin, for
which patients experiencing a dose change were
slightly more common in the levetiracetam group); (3)
if levetiracetam affected the serum concentration of a
concomitant AED, this pattern should have emerged
at least as a trend among patients in whom the dosage
of comedication remained unchanged. Taken together,
these data confirm that levetiracetam is unlikely
to interact with concomitant AEDs, either through
induction of their metabolism or inhibition of their
elimination. Consequently, from a pharmacokinetic 此段主要从另一个
perspective, changes in background AED dosage 角度进一步说明文
would not be anticipated when levetiracetam 章主题，即从药代 is
added to or removed from an existing medication 动力学角度说明左
regimen.
Evidence for the lack of a significant influence
乙拉西坦不会影响
of levetiracetam on the serum concentration of con- 血清药物浓度
currently administered drugs is strengthened by the
results of formal interaction studies in vitro and in
vivo. In vitro, levetiracetam, tested at therapeutically
relevant concentrations, has been shown not to in-
hibit a variety of drug metabolizing enzymes, includ-
ing cytochrome P (CYP) 3A4, CYP1A2, CYP2C19,
CYP2E1, CYP2C9, CYP2D6, epoxide hydrolase, and
various isoforms of uridine-5 -diphospho-glucuronyl-
transferases (Patsalos, 2000; Nicolas et al., 1999). In
healthy volunteers or in patients with epilepsy, leve-
tiracetam was equally found not to affect the pharma-
cokinetic profile of phenytoin (Browne et al., 2000),
digoxin (Levy et al., 2001), S-warfarin (Ragueneau-
Majlessi et al., 2001), and steroid oral contraceptives
(Ragueneau-Majlessi et al., 2002).
 没有测定没有测定大
多数患者氨己烯酸的
血清浓度，两者之间
的用药反应等，这都
10 是本文的软肋。
B.E. Gidal et al. / Epilepsy Research 64 (2005) 1–11
Serum concentrations of vigabatrin were not deter-
mined in most patients comedicated with this drug.
Although the ratio of geometric means of vigabatrin
serum concentrations during adjunctive levetiracetam
treatment compared with baseline did not suggest any
major interaction between these drugs, due to the small
number of observations, 90% confidence intervals for
this ratio exceeded the 80–125% limits, indicating that
data concerning any influence (or lack of influence)
of levetiracetam on serum levels of vigabatrin should
be regarded as preliminary. Given that vigabatrin is pri-
marily eliminated by renal excretion as unchanged par-
ent drug, one would not, however, predict an interaction
between these two agents.
The influence of concomitant AEDs on the phar-
macokinetics of levetiracetam has been determined in
a complementary analysis that has been reported else-
where (Perucca et al., 2003). The analysis showed that
serum levetiracetam concentrations were not affected
to any great extent by the concomitant use of other
AEDs. The concentration of levetiracetam tended to
be lower and its half-life shorter among patients re-
历史数据支持 ceiving AEDs known to be enzyme inducers (e.g., car-
bamazepine, phenytoin, phenobarbital, and primidone)
compared with those that are considered to have little
effect on drug metabolizing enzymes (e.g., gabapentin,
lamotrigine, and vigabatrin). However, the differences
were small and of doubtful clinical significance, and the
half-life of levetiracetam was within the 6–8-h range
reported in formal pharmacokinetic studies. For pa-
tients receiving concomitant valproic acid, a drug that
may inhibit some drug metabolizing enzymes, leve-
tiracetam concentrations tended to be higher and its
half-life longer, but again, the differences relative to
AED comedications with little effect on drug metab-
olizing enzymes were modest and unlikely to be of
clinical significance. On the basis of this analysis and
additional formal drug interactions studies (Coupez
et al., 2003; Patsalos et al., 2002), it was concluded
there are no reasons to anticipate any difference in lev-
etiracetam dosage requirements in relation to the type
of underlying AED medication (Perucca et al., 2003).
5 Conclusions
This pooled analysis demonstrates that adjunctive
levetiracetam therapy in patients with refractory partial
seizures does not significantly affect the steady-state
serum concentrations of concomitantly administered
carbamazepine, phenytoin, valproic acid, lamotrigine,
gabapentin, phenobarbital, or primidone. On the
basis of these findings, pharmacokinetic interactions
requiring dose adjustments are not anticipated when
levetiracetam is prescribed in combination with these
AEDs.
结论：左乙拉西坦
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