Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects
Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects
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DOI：
10.1046/j.1365-2125.1997.t01-1-00612.x
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发表时间：
1997-11-01
影响因子：
3.4
通讯作者：
Cohen, AF
中科院分区：
文献类型：
--
作者：
Dingemanse, J;vanGerven, JMA;Cohen, AF
目的本研究旨在探讨递增剂量的Ro 48 - 671的药代动力学和药效学，与咪达唑仑相比，在健康受试者首次给药的小型研究方法本研究是双盲和五向交叉治疗连续5天（三个递增剂量，安慰剂，固定剂量咪达唑仑）在两个连续组的5名健康男性受试者。Ro 48 - 6791缓慢静脉输注给药，第一次给药汤剂量为0.1 - 0.3 - 1 mg，第二次给药汤剂量为1 - 2 - 3 mg。咪达唑仑以0.1 mg/kg输注。输注在20分钟后停止，或者如果镇静作用变得太强而无法正确进行测试，则停止输注。因此，不同剂量之间的输注速率（mg/min）差异很大。频繁采集血样用于药代动力学测定（二室模型）。通过记录扫视眼球运动（扫视峰值速度）和脑电图（β功率）评估药效学。结果Ro 48 - 6791和咪达唑仑均耐受良好。大多数临床事件是剂量依赖性的中枢神经系统效应。Ro 48 - 6791的平均分布容积（V-ss）和血浆清除率明显大于咪达唑仑（分别为171 +/-65 vs 41 +/-10 l和2.2 +/-0.9 vs 0.42 +/-0.11 l min（-1））。导致扫视眼球运动丧失的Ro 48 - 6791剂量平均比咪达唑仑低4倍。相应的预测效应室浓度相差约6倍。Ro 48 - 6791和咪达唑仑剂量引起的最大效应相似，对扫视峰值速度的起效时间和作用持续时间相似。在最高给药剂量下，咪达唑仑引起的β-功率增加显著大于Ro 48 - 6791（33%，范围17，55%）。Ro 18 - 6792是Ro 48 - 6791的代谢产物，其半衰期明显长于母体化合物。虽然没有迹象表明，在本研究中的RO 48 - 6792的可辨别的效果，在长期给药过程中可能积累的影响应进一步investigated.Conclusions这第一次研究与RO 48 - 6791在人类已表明，这苯二氮卓类药物是大约4至6倍的有效咪达唑仑，但具有可比的发病和持续时间的行动。
Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48-671, compared with midazolam, in healthy subjects during first administration to mall studies.Methods The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48-6791 was administered as a slow i.v. infusion in doses of 0.1-0.3-1 mg in the first soup, and 1-2-3 mg in the second. Midazolam was infused at 0.1 mg kg. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (beta-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling.Results Ro 48-6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V-ss) and plasma clearance of Ro 48-6791 were on average markedly larger than those of midazolam (171 +/- 65 vs 41 +/- 10 l and 2.2 +/- 0.9 vs 0.42 +/- 0.11 l min(-1), respectively). The doses of Ro 48-6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48-6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action fbr saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in beta-power than Ro 48-6791 at the highest administered dose. Ro 18-6792, a metabolite of Ro 48-6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48-6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further.Conclusions This first study with Ro 48-6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.