健康中国男性志愿者单剂量给药后盐酸克林霉素制剂的药代动力学和生物等效性研究

Pharmacokinetics and bioequivalence study of clindamycin hydrochloride formulations after single-dose administration in healthy Chinese male volunteers.

作者信息

Li Jing, Wang Na, Zhang Zun-Jian, Tian Yuan, Tang Weiguo, Chen Yun

机构信息

Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing, PR China.

出版信息

Arzneimittelforschung. 2008;58(7):358-62. doi: 10.1055/s-0031-1296520.

Abstract

The aim of the present study was to compare the bioavailability of clindamycin (CAS 18323-44-9) from three clindamycin hydrochloride (CAS 21 462-39-5) capsules (clindamycin 75 mg capsule as test 1 preparation, 150 mg capsule as test 2 preparation and a commercially available original 150 mg capsule of the drug as reference preparation) in 24 Chinese healthy male volunteers, aged between 22 and 28. The study was conducted according to a randomized, double-blind, 3-period, 3-treatment, 3-sequence, single-dose, crossover design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 14 h post-dose, and clindamycin plasma concentrations were determined with a validated liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Maximum plasma concentrations (C(max)) of 3.06 +/- 1.10 microg/mL (test 1), 3.10 +/- 1.59 microg/mL (test 2) and 3.06 +/- 1.15 microg/mL (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 10.73 +/- 4.29 microg x h/mL (test 1), 10.54 +/- 4.10 microg x h/ mL (test 2) and 11.29 +/- 4.98 microg x h/mL (reference), AUC(0-t) of 10.32 +/- 4.09 microg x h/ mL, 10.26 +/- 3.96 microg x h/mL, 10.94 +/- 4.86 g x h/mL were calculated. The median T(max) was 0.80 +/- 0.52 h, 0.77 +/- 0.37 h, 1.01 +/- 0.6 h for test 1, test 2 and reference formulation, respectively. Plasma elimination half-lives (t1/2) of 2.72 +/- 0.58 h (test 1), 2.39 +/- 0.37 h (test 2) and 2.63 +/- 0.66 h (reference) were determined. Both primary target parameters, AUC(0-infinity) and AUC(0-t) were tested parametrically by analysis of variance (ANOVA) and relative bioavailabilities were 98.0 +/- 16.2% (test 1) and 97.2 +/- 20.3% (test 2) for AUC(0-infinity), 97.5 +/- 16.3% (test 1) and 97.8 +/- 20.2% (test 2) for AUC(0-t). Bioequivalence between test and reference preparation was demonstrated for both parameters, AUC(0-infinity) and AUC(0-t). The 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%. That means that the two test formulations are bioequivalent to the reference formulation for clindamycin.

摘要

本研究旨在比较三种盐酸克林霉素(CAS 21462-39-5)胶囊(75mg克林霉素胶囊作为试验1制剂,150mg胶囊作为试验2制剂,市售的150mg原研药胶囊作为参比制剂)中克林霉素(CAS 18323-44-9)在24名年龄在22至28岁之间的中国健康男性志愿者体内的生物利用度。本研究按照随机、双盲、3周期、3治疗、3序列、单剂量、交叉设计进行,洗脱期为7天。给药后长达14小时采集血样进行药代动力学分析,采用经过验证的液相色谱-电喷雾电离-质谱(LC-ESI-MS)法测定克林霉素血浆浓度。试验1制剂、试验2制剂和参比制剂的最大血浆浓度(C(max))分别为3.06±1.10μg/mL、3.10±1.59μg/mL和3.06±1.15μg/mL。计算血浆浓度-时间曲线下面积(AUC(0-∞)),试验1制剂、试验2制剂和参比制剂分别为10.73±4.29μg·h/mL、10.54±4.10μg·h/mL和11.29±4.98μg·h/mL,AUC(0-t)分别为10.32±4.09μg·h/mL、10.26±3.96μg·h/mL、10.94±4.86μg·h/mL。试验1制剂、试验2制剂和参比制剂的中位达峰时间(T(max))分别为0.80±0.52小时、0.77±0.37小时和1.01±0.6小时。测定血浆消除半衰期(t1/2),试验1制剂、试验2制剂和参比制剂分别为2.72±0.58小时、2.39±0.37小时和2.63±0.66小时。两个主要目标参数AUC(0-∞)和AUC(0-t)采用方差分析(ANOVA)进行参数检验,AUC(0-∞)的相对生物利用度试验1制剂为98.0±16.2%,试验2制剂为97.2±20.3%;AUC(0-t)的相对生物利用度试验1制剂为97.5±16.3%,试验2制剂为97.8±20.2%。试验制剂与参比制剂在AUC(0-∞)和AUC(0-t)这两个参数上均显示生物等效性。对数转换数据的T/R比的90%置信区间在普遍接受范围80%-125%内。这意味着两种试验制剂在克林霉素方面与参比制剂生物等效。

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