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摘要:
目的 研究单次和多次服用60或120 mg抗焦虑药布格呋喃的药代动力学及药效学特征。 方法 试验为随机、双盲、安慰剂对照、平行组设计, 在布格呋喃60 mg组和120 mg组分别纳入14名中国健康受试者, 男女各7名。每个剂量组中, 男性和女性受试者随机接受布格呋喃胶囊或安慰剂治疗的比例均为5:2。受试者在研究第1天给药1次, 48 h后, 在研究第3天起每天2次给药, 连续4.5 d。在首次及末次给药后, 分别按照方案规定的时间点连续采集血液和尿液药代动力学样本至给药后48 h, 同时进行躯体摆动、选择反应时间、数字广度、视觉类比量表(visual analogue scale, VAS)等药效学测试。 结果 单次口服60或120 mg布格呋喃后, 其药代动力学参数的平均值分别为:血浆峰浓度Cmax(37.7±18.4)和(95.8±34.8)ng/ml, 零至最后一个可定量时间点血浆浓度-时间曲线下面积AUC0-t为(108±46)和(336±104)h·ng/ml, 表观清除率为(581±203)L/h和(367±122)L/h, 消除相半衰期t1/2为(10.4±7.1)和(19.8±6.5)h。在每日2次重复给药4.5 d后, 60 mg组和120 mg组布格呋喃的平均Cmax分别为(48.5±32.2)和(118.0±20.3)ng/ml, AUC0-t分别为(241±122)和(656±135)h·ng/ml。除VAS清醒度、VAS外在感受和VAS内在感受外, 本研究检测的绝大多数药效学指标在单次和多次给药后与其他给药组间的差异均无统计学意义(P均 > 0.05)。 结论 每日2次、连续口服布格呋喃约24 h后, 其血浆暴露水平达到稳态, 较单次给药后有2~3倍蓄积。口服60或120 mg布格呋喃在健康受试者中的安全性和耐受性良好。研究选用的药效学指标呈阴性, 可能与药效学方法验证欠充分相关。 Abstract:Objective To investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of buagafuran after single, and twice-daily repeated oral doses of 60 or 120 mg. Methods In this double-blind, randomized, placebo-controlled, parallel study, 7 male and 7 female healthy subjects were enrolled in each dosing cohort and were administered with buagafuran or placebo based on a 5:2 randomized allocation schedule. Subjects took a single oral dose of buagafuran or placebo on the first day. After 48 hours, subjects started to receive twice daily repeated administration for 4.5 days. Within the 48 hours following the first and the last study doses, the serial blood and urine samples were collected for PK assays. Meanwhile, PD measurements were performed, which included body sway, choice reaction time, digit span task, visual analogue scale (VAS) of Bond and Lader, and VAS of Bowdle. Results After the single oral dose of buagafuran, the mean PK parameters were: Cmax, (37.7±18.4) ng/ml and (95.8±34.8) ng/ml; area under the plasma concentration-time curve (AUC)0-t, (108±46) h·ng/ml and (336±104) h·ng/ml; apparent clearance, (581±203) L/h and (367±122) L/h; t1/2, (10.4±7.1) hours and (19.8±6.5) hours for 60 and 120 mg buagafuran, respectively. With twice daily repeated administration for 4.5 days, the mean Cmax were (48.5±32.2) ng/ml and (118.0±20.3) ng/ml, with a mean AUC0-t of (241±122) h·ng/ml and (656±135) h·ng/ml for 60 and 120 mg, respectively. No PD parameters showed clinically or statistically significant difference between these two dosing schemes except for VAS alertness, VAS external feeling, and VAS internal feeling. Conclusions The plasma exposure of buagafuran attains a steady state with approximately 2-3 times of accumulation after twice-daily repeated dosing for 24 hours. The oral administrations with 60 or 120 mg buagafuran were safe and well tolerated in the healthy subjects. The absence of PD findings may be attributed to the insufficient validation of the PD measurements. -
Key words:
- buagafuran /
- anxiety /
- pharmacokinetics /
- pharmacodynamics
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表 1 受试者的人口统计学资料
表 2 中枢神经系统药效学测试
表 3 单次口服60、120mg布格呋喃胶囊或安慰剂后各药效学指标相对基线的总体变化量
表 4 每日2次口服60、120mg布格呋喃胶囊或安慰剂后各药效学指标相对基线的总体变化量
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[1] Yang F, Wang H, Peng A, et al. Quantitative determination of buagafuran in human plasma by liquid chromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2011, 879:1789-1794. doi: 10.1016/j.jchromb.2011.04.029 [2] Bond A, Lader M. The use of analogue scales in rating subjective feelings[J]. Br J Med Psychol, 1974, 47:211-218. doi: 10.1111/j.2044-8341.1974.tb02285.x [3] Bowdle TA, Radant AD, Cowley DS, et al. Psychedelic effects of ketamine in healthy volunteers:relationship to steady-state plasma concentrations[J]. Anesthesiology, 1998, 88:82-88. doi: 10.1097/00000542-199801000-00015 [4] de Visser SJ, van der Post JP, de Waal PP, et al. Biomarkers for the effects of benzodiazepines in healthy volunteers[J]. Br J Clin Pharmacol, 2003, 55:39-50. doi: 10.1046/j.1365-2125.2002.t01-10-01714.x [5] Chen X, de Haas S, de Kam M, et al. An overview of the CNS-pharmacodynamic profiles of nonselective and selective GABA agonists[J]. Adv Pharmacol Sci, 2012:134523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3273701/ [6] 《化学药物临床药代动力学研究技术指导原则》课题研究组.化学药物临床药代动力学研究技术指导原则[M].北京:国家食品药品监督管理局药品注册审评中心, 2005:9. -
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