Jang Jae-Won, Seo Ji-Hyung, Jo Min-Ho, Lee Young-Joo, Cho Young-Wuk, Yim Sung-Vin, Lee Kyung-Tae
Department of Pharmaceutical Biochemistry, College of Pharmacy, College of Medical Science, Kyung Hee University, Seoul, Republic of Korea.
Int J Clin Pharmacol Ther. 2013 Feb;51(2):152-60. doi: 10.5414/cp201730.
Levodropropizine is an oral non-opioid anti-tussive drug used in treatment of cough. A new generic 60 mg capsule formulation of levodropropizine has recently been developed.
The aim of this study was to assess the pharmacokinetics and bioequivalence of the test (capsule) formulation and reference (syrup) formulation of levodropropizine (60 mg) in healthy, fasted, male Korean volunteers.
This was a single-dose, randomized sequence, open-label, 2-period crossover study conducted in healthy male Korean volunteers in the fasted state at Kyung Hee University Medical Center (Seoul, Republic of Korea). A single oral dose of the test or reference formulation was followed by a 1-week washout period, after which subjects received the alternative formulation. Blood samples were collected at 0 (predose), 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after study drug administration. Plasma concentration of levodropropizine was determined using a validated liquid chromatography tandem mass spectrometry (LCMS/ MS) method. The formulations were considered bioequivalent if the 90% CIs for C(max), AUC(0-12h) and AUC(0-∞) were within the predetermined bioequivalence range (80 - 125%, according to the guidelines of the Korea Food and Drug Administration (Korea FDA)). Tolerability was evaluated throughout the study based on vital sign measurements, laboratory analysis (blood biochemistry, hematology, hepatic function and urinalysis) and subject interviews concerning adverse events (AEs).
A total of 36 male Korean subjects (mean (SD) age, 23.9 (2.4) years (range 19 - 30 years); height, 176.2 (6.1) cm (range 161 - 190 cm); weight, 69.8 (9.1) kg (range 54.0 - 92.2 kg); body mass index, 22.4 (2.1) kg/m2 (range 19.1 - 28.3 kg/m2)) was enrolled and completed the study. The mean values for C(max), t(max), AUC(0-12h), and AUC(0-∞) with the test formulation of levodropropizine were 331.51 ng/ml, 0.60 hours, 784.32 ng×h/ml, and 825.82 ng×h/ml, respectively; for the reference formulation, the values were 332.81 ng/ml, 0.44 hours, 726.46 ng×h/ml, and 769.46 ng×h/ ml, respectively. The 90% CIs for the logtransformed ratios of C(max) (92.74 - 111.24), AUC(0-12h) (104.31 - 113.67) and AUC(0-∞) (103.87 - 113.57) were within the predetermined range for the assumption of bioequivalence. No serious adverse events were reported.
This single-dose (60 mg) study found that the test (capsule) and reference (syrup) formulations of levodropropizine met the regulatory criterion for assuming bioequivalence in these healthy, fasted, male Korean subjects. Both formulations were well tolerated in the population studied. Korea FDA registration number: BED-1784.
左羟丙哌嗪是一种用于治疗咳嗽的口服非阿片类镇咳药物。最近开发了一种新的左羟丙哌嗪60毫克胶囊仿制药制剂。
本研究旨在评估左羟丙哌嗪（60毫克）的试验（胶囊）制剂和参比（糖浆）制剂在健康、空腹的韩国男性志愿者中的药代动力学和生物等效性。
这是一项在韩国庆熙大学医学中心（韩国首尔）对处于空腹状态的健康韩国男性志愿者进行的单剂量、随机序列、开放标签、两周期交叉研究。单次口服试验制剂或参比制剂后有1周的洗脱期，之后受试者接受另一种制剂。在研究药物给药后的0（给药前）、0.17、0.33、0.5、0.75、1、1.5、2、3、4、6、8和12小时采集血样。使用经过验证的液相色谱串联质谱（LCMS/MS）方法测定左羟丙哌嗪的血浆浓度。如果C(max)、AUC(0 - 12h)和AUC(0 - ∞)的90%置信区间在预定的生物等效性范围内（根据韩国食品药品管理局（韩国FDA）的指南为80 - 125%），则认为两种制剂具有生物等效性。在整个研究过程中，基于生命体征测量、实验室分析（血液生化、血液学、肝功能和尿液分析）以及关于不良事件（AE）的受试者访谈来评估耐受性。
共有36名韩国男性受试者（平均（标准差）年龄23.9（2.4）岁（范围19 - 30岁）；身高176.2（6.1）厘米（范围161 - 190厘米）；体重69.8（9.1）千克（范围54.0 - 92.2千克）；体重指数22.4（2.1）千克/平方米（范围19.1 - 28.3千克/平方米））入组并完成研究。左羟丙哌嗪试验制剂的C(max)、t(max)、AUC(0 - 12h)和AUC(0 - ∞)的平均值分别为331.51纳克/毫升、0.60小时、784.32纳克·小时/毫升和825.82纳克·小时/毫升；参比制剂的相应值分别为332.81纳克/毫升、0.44小时、726.46纳克·小时/毫升和769.46纳克·小时/毫升。C(max)（92.74 - 111.24）、AUC(0 - 12h)（104.31 - 113.67）和AUC(0 - ∞)（103.87 - 113.57）的对数转换比值的90%置信区间在假定生物等效性的预定范围内。未报告严重不良事件。
这项单剂量（60毫克）研究发现，左羟丙哌嗪的试验（胶囊）制剂和参比（糖浆）制剂在这些健康、空腹的韩国男性受试者中符合假定生物等效性的监管标准。两种制剂在所研究的人群中耐受性良好。韩国FDA注册号：BED - 1784。
