Fay Monica A, Sheth Raj D, Gidal Barry E
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, USA.
Clin Ther. 2005 May;27(5):594-8. doi: 10.1016/j.clinthera.2005.05.010.
Levetiracetam (LEV) is an antiepileptic drug with a favorable pharmacokinetic profile, including negligible protein binding and linear elimination kinetics. Because LEV is likely to be used in populations that include children and the elderly, alternative techniques of administration, such as crushing the tablet and mixing its contents with semisolid food or enteral nutrition formulas (ENFs), may be required in some clinical settings. Although previous studies have suggested that administration with food does not affect the overall absorption of LEV, there is a lack of data regarding concomitant administration with ENFs.
The objective of this study was to evaluate the oral absorption of LEV after concomitant administration with food or ENFs.
This was an unblinded, 3-way crossover study. After an overnight fast, subjects received a single dose of LEV 500 mg administered either as an intact tablet with 120 mL water (control, treatment A) or crushed and mixed with 4 oz applesauce (treatment B) or 120 mL of a common ENF (treatment C). All subjects received each treatment in a randomized sequence; there was a 7-day washout period between treatments. Serial blood samples were obtained over 24 hours for determination of the LEV serum concentration-time profile using gas chromatography with nitrogen phosphorus detection. AUC(0-24), C(max), and T(max) were calculated using noncompartmental methods and analyzed using analysis of variance.
Ten healthy adult volunteers (6 men, 4 women) participated in the study (mean [SD] age, 28.9 [6.5] years; mean body weight, 78.6 [12.9] kg). No significant differences were noted between control and any other study treatment. Mean AUC values were 191.9 (50.2), 165.7 (43.4), and 168.3 (43.9) microg/mL . h for treatments A, B, and C, respectively. Mean T(max) values were 1.08 (0.65), 1.32 (0.75), and 1.62 (0.73) hours, respectively. Mean C(max) values were 14.8 (5.6), 12.1 (2.8), and 10.8 (2.0) microg/mL for the respective treatments. Mean LEV serum concentrations at 12 hours after dosing were similar for all study treatments (3.9, 4.1, and 4.0 microg/mL). The long-term stability of LEV in the various combinations was not assessed.
In these healthy volunteers, the overall rate and extent of absorption of oral LEV were not significantly impaired after crushing and mixing of the tablet with either a food vehicle or a typical ENF product. The data suggest that peak serum concentrations of LEV may be slightly reduced after mixing with ENFs, although the difference was not significant compared with control values.
左乙拉西坦（LEV）是一种抗癫痫药物，具有良好的药代动力学特征，包括可忽略不计的蛋白结合率和线性消除动力学。由于LEV可能用于包括儿童和老年人在内的人群，在某些临床情况下可能需要采用其他给药技术，如将片剂碾碎并将其内容物与半固体食物或肠内营养配方（ENF）混合。尽管先前的研究表明与食物一起给药不会影响LEV的总体吸收，但缺乏关于与ENF同时给药的数据。
本研究的目的是评估与食物或ENF同时给药后LEV的口服吸收情况。
这是一项非盲法、三交叉研究。经过一夜禁食后，受试者接受单剂量500mg的LEV，给药方式为：作为完整片剂与120mL水一起服用（对照，治疗A），或碾碎后与4盎司苹果酱混合（治疗B），或与120mL普通ENF混合（治疗C）。所有受试者按随机顺序接受每种治疗；治疗之间有7天的洗脱期。在24小时内采集系列血样，使用带氮磷检测的气相色谱法测定LEV血清浓度-时间曲线。使用非房室方法计算AUC(0-24)、C(max)和T(max)，并使用方差分析进行分析。
10名健康成年志愿者（6名男性，4名女性）参与了研究（平均[标准差]年龄，28.9[6.5]岁；平均体重，78.6[12.9]kg）。对照与任何其他研究治疗之间未观察到显著差异。治疗A、B和C的平均AUC值分别为191.9(50.2)、165.7(43.4)和168.3(43.9)μg/mL·h。平均T(max)值分别为1.08(0.65)、1.32(0.75)和1.62(0.73)小时。各治疗的平均C(max)值分别为14.8(5.6)、12.1(2.8)和10.8(2.0)μg/mL。所有研究治疗在给药后12小时的平均LEV血清浓度相似（3.9、4.1和4.0μg/mL）。未评估LEV在各种组合中的长期稳定性。
在这些健康志愿者中，将片剂与食物载体或典型的ENF产品碾碎并混合后，口服LEV的总体吸收速率和程度未受到显著损害。数据表明，与ENF混合后LEV的血清峰值浓度可能会略有降低，尽管与对照值相比差异不显著。
