食物对健康受试者单次和多次服用氢可酮缓释制剂药代动力学的影响。

Effect of Food on the Pharmacokinetics of Single- and Multiple-Dose Hydrocodone Extended Release in Healthy Subjects.

作者信息

Bond Mary, Rabinovich-Guilatt Laura, Selim Sally, Darwish Mona, Tracewell William, Robertson Philmore, Yang Ronghua, Malamut Richard, Colucci Philippe, Ducharme Murray P, Spiegelstein Ofer

机构信息

Teva Pharmaceuticals, 2 West Liberty Blvd, Malvern, PA, 19355, USA.

Teva Pharmaceuticals, 41 Moores Road, Frazer, PA, 19355, USA.

出版信息

Clin Drug Investig. 2017 Dec;37(12):1153-1163. doi: 10.1007/s40261-017-0575-3.

DOI:10.1007/s40261-017-0575-3

PMID:28948482

Abstract

BACKGROUND AND OBJECTIVES

Food intake can alter the pharmacokinetics of certain medications, including changes in their oral bioavailability, which is of particular concern for extended-release (ER) opioids because of the high drug loads. Two randomized, open-label studies assessed the effect of food on the pharmacokinetics of single and multiple doses of hydrocodone ER formulated with CIMA Abuse-Deterrence Technology.

METHODS

Healthy subjects in fed and fasted states received single 90-mg doses of hydrocodone ER (Studies 1 and 2) or multiple doses of hydrocodone ER (45 mg twice daily on days 2-3, 60 mg twice daily on days 4-5, 90 mg twice daily on days 6-10, and 90 mg once in the morning on day 11) (Study 2). Naltrexone was administered to minimize opioid-related adverse events. Pharmacokinetic parameters included maximum hydrocodone plasma concentration (C ) and area under the concentration-versus-time curve from time 0 to infinity (AUC) in Study 1 (day 1) and for one dosing interval at steady state (AUC) in Study 2 (day 11). Before conducting the multiple-dose study, single-dose data were fitted with a population pharmacokinetic methodology.

RESULTS

In total, 40 subjects were randomized to Study 1 and 43 subjects were randomized to Study 2. While overall exposure (AUC) was relatively similar (least squares mean ratio [90% CI]: 1.11 [1.06-1.16]), results indicated that the single-dose C was 40% higher under fed versus fasted conditions (least squares mean ratio [90% CI]: 1.40 [1.31-1.51]; Study 1). Modeling of single-dose data predicted that the effect of food would be much less at steady state [predicted fed:fasted C at steady state (C ) and AUC ratios of 1.18 and 1.09, respectively]. The multiple-dose study results validated these predicted ratios and indicated that the steady-state 90% CIs were within 0.80-1.25 for the fed:fasted C (1.14 [1.07-1.21]) and AUC (1.11 [1.04-1.17]) parameters, indicating that clinically meaningful food effects at steady state are not expected.

CONCLUSION

No evidence of an effect of food was found on the pharmacokinetics of hydrocodone ER after multiple days of twice-daily dosing.

摘要

背景与目的

食物摄入可改变某些药物的药代动力学，包括其口服生物利用度的变化，对于高剂量的缓释（ER）阿片类药物而言，这一点尤为值得关注。两项随机、开放标签研究评估了食物对采用CIMA防滥用技术配制的单剂量和多剂量氢可酮ER药代动力学的影响。

方法

处于进食和禁食状态的健康受试者接受单剂量90毫克的氢可酮ER（研究1和2）或多剂量氢可酮ER（第2 - 3天每日两次，每次45毫克；第4 - 5天每日两次，每次60毫克；第6 - 10天每日两次，每次90毫克；第11天上午一次，90毫克）（研究2）。给予纳曲酮以尽量减少阿片类药物相关不良事件。药代动力学参数包括研究1（第1天）中氢可酮的最大血浆浓度（C）以及浓度 - 时间曲线从0至无穷大的面积（AUC），和研究2（第11天）中稳态下单剂量间隔的AUC。在进行多剂量研究之前，单剂量数据采用群体药代动力学方法进行拟合。

结果

共有40名受试者被随机分配至研究1，43名受试者被随机分配至研究2。虽然总体暴露量（AUC）相对相似（最小二乘均值比[90%置信区间]：1.11[1.06 - 1.16]），但结果表明，进食条件下单剂量C比禁食条件下高40%（最小二乘均值比[90%置信区间]：1.40[1.31 - 1.51]；研究1）。单剂量数据建模预测，食物在稳态下影响会小得多[预测进食：禁食稳态下的C（C）和AUC比值分别为1.18和1.09]。多剂量研究结果验证了这些预测比值，并表明进食：禁食C（1.14[1.07 - 1.21]）和AUC（1.11[1.04 - 1.17]）参数的稳态90%置信区间在0.80 - 1.25范围内，表明稳态下不存在具有临床意义的食物效应。