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丙戊酸钠到丙戊酸钠缓释剂型的转换。

Divalproex to divalproex extended release conversion.

机构信息

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA.

出版信息

Clin Drug Investig. 2004;24(9):495-508. doi: 10.2165/00044011-200424090-00001.

Abstract

OBJECTIVE

Divalproex extended release (ER) tablets have lower bioavailability than conventional divalproex tablets. Objectives were to provide dose-increment justification for conversion of a patient from conventional enteric-coated divalproex to a once-daily divalproex ER regimen and to discuss the pharmacokinetic factors affecting these unequal total daily dose conversions.

METHODS

Three bioavailability studies (two in healthy volunteers and one in epilepsy patients; total n = 69) compared equal total daily doses, and two studies (one each in healthy volunteers and epilepsy patients; total n = 99) compared 8-20% higher divalproex ER daily doses with corresponding divalproex total daily doses. In all five studies, multiple doses were administered over 6-14 days in each regimen.

RESULTS

For equal total daily dose comparisons, the divalproex ER/divalproex bioavailability (area under the concentration-time curve [AUC] ratio) was ~0.89 and when the divalproex ER dose was higher, the two regimens were equivalent (AUC ratio ~1.0). Divalproex ER administered once daily had less fluctuation in valproic acid concentrations, i.e. divalproex ER achieved equal or significantly higher minimum concentrations and significantly lower maximum concentrations compared with divalproex administered multiple times daily. Divalproex ER predose trough concentration consistently represented the lowest concentration during a dosing interval, whereas for divalproex this was not true because of absorption lag time (from enteric coating), diurnal variation and multiple doses during a 24-hour interval.

CONCLUSIONS

An 8-20% higher divalproex ER daily dose should be used when converting from a total daily dose of divalproex. The lower fluctuation of valproic acid concentrations, consistent time to trough concentration, and lower dosing frequency of divalproex ER should offer benefit to the patient by providing convenient once-daily administration, and to the clinician by facilitating easier and reliable therapeutic drug monitoring and improving patient adherence.

摘要

目的

丙戊酸钠缓释片(ER)的生物利用度低于传统丙戊酸钠片。目的是为患者从传统的肠包衣丙戊酸钠转换为每日一次的丙戊酸钠 ER 方案提供剂量递增的理由,并讨论影响这些不等总日剂量转换的药代动力学因素。

方法

三项生物利用度研究(两项在健康志愿者中进行,一项在癫痫患者中进行;总 n = 69)比较了相等的总日剂量,两项研究(一项在健康志愿者中进行,一项在癫痫患者中进行;总 n = 99)比较了 8-20%更高的丙戊酸钠 ER 日剂量与相应的丙戊酸钠总日剂量。在所有五项研究中,每个方案均在 6-14 天内给予多次剂量。

结果

对于相等的总日剂量比较,丙戊酸钠 ER/丙戊酸钠的生物利用度(浓度-时间曲线下面积[AUC]比值)约为 0.89,当丙戊酸钠 ER 剂量较高时,两种方案等效(AUC 比值约为 1.0)。每日一次给予丙戊酸钠 ER 时,丙戊酸浓度波动较小,即丙戊酸钠 ER 达到或显著更高的最低浓度,并显著降低了与每日多次给予丙戊酸钠相比的最高浓度。丙戊酸钠 ER 给药前谷浓度始终代表一个剂量间隔内的最低浓度,而对于丙戊酸钠,由于吸收滞后(来自肠包衣)、昼夜变化和 24 小时内的多次剂量,这并非如此。

结论

从丙戊酸钠的总日剂量转换时,应使用 8-20%更高的丙戊酸钠 ER 日剂量。丙戊酸浓度波动较小、谷浓度时间一致、丙戊酸钠 ER 给药频率较低,为患者提供方便的每日一次给药,为临床医生提供更方便、更可靠的治疗药物监测,并提高患者的依从性,这将为患者带来益处。

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