对健康志愿者逐渐增加静脉注射剂量后，一种新型超短效钙拮抗剂氯维地平的临床及药代动力学结果。
Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers.
作者信息
Ericsson H, Fakt C, Jolin-Mellgård A, Nordlander M, Sohtell L, Sunzel M, Regårdh C G
机构信息
Astra Hässle Research Laboratories, Astra Hässle AB, S-431 86 Mölndal, Sweden.
出版信息
Br J Clin Pharmacol. 1999 May;47(5):531-8. doi: 10.1046/j.1365-2125.1999.00933.x.
AIMS
To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug.
METHODS
Twenty-five subjects were enrolled in the study and twenty-one of them were included twice, resulting in a total of forty-six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 0.12 to 48 nmol min-1 kg-1. Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were evaluated by non-compartmental and compartmental analysis. An Emax model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine.
RESULTS
Clevidipine was administered up to a target dose rate of 48 nmol min-1 kg-1, where a pre-determined escape criterion was reached (HR>120 beats min-1 ) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non-compartmental analysis was 0.125 l min-1 kg-1. Applying the population approach to the sparse data on clevidipine concentrations, an open two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.121 l min-1 kg-1, and the volume of distribution at steady state was 0.56 l kg-1. The initial half-life, contributing by more than 80% to the total area under the blood concentration-time curve following i.v. bolus administration, was 1.8 min, and the terminal half-life was 9.5 min. At the highest dose rates, MAP was reduced by approximately 10%, and the HR reached the pre-determined escape criterion for this study (>120 beats min-1 ).
CONCLUSIONS
Clevidipine is well tolerated and safe in healthy volunteers at dose rates up to at least 48 nmol min-1 kg-1. The pharmacokinetics are linear over a wide dose range. Clevidipine is a high clearance drug with extremely short half-lives. The effect of clevidipine on the blood pressure was marginal, probably due to a compensatory baroreflex activation in this population of healthy volunteers. A simple Emax model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blood concentrations of clevidipine.
目的
研究在健康男性志愿者中，按逐渐递增的剂量率静脉输注时，克立夫定的耐受性和安全性，并获取该药物的药代动力学和药效学效应的初步信息。
方法
25名受试者参与本研究，其中21名受试者参与了两次，因此共有46次研究记录，包括以0.12至48 nmol·min⁻¹·kg⁻¹的目标剂量率静脉输注克立夫定20分钟。在整个研究过程中记录血流动力学变量和不良事件。跟踪全血中克立夫定及其主要代谢产物H 152/81的浓度，并通过非房室分析和房室分析评估药代动力学。将Emax模型拟合到平均动脉压（MAP）对心率（HR）以及相应的克立夫定血药浓度的影响上。
结果
克立夫定的给药剂量率最高达到48 nmol·min⁻¹·kg⁻¹，此时达到了预先设定的逸出标准（HR>120次/分钟），研究终止。最常见的不良事件是潮红和头痛，这可能与克立夫定的作用机制直接相关。在所研究的剂量范围内，血药浓度与剂量率之间呈线性关系。通过非房室分析确定的中位清除率值为0.125 l·min⁻¹·kg⁻¹。将群体方法应用于克立夫定浓度的稀疏数据，发现开放二室药代动力学模型是描述该药物处置的最佳模型。通过该方法确定的群体平均清除率值为0.121 l·min⁻¹·kg⁻¹，稳态分布容积为0.56 l·kg⁻¹。静脉推注给药后，初始半衰期对血药浓度-时间曲线下总面积的贡献超过80%，为1.8分钟，终末半衰期为9.5分钟。在最高剂量率下，MAP降低了约10%，HR达到了本研究预先设定的逸出标准（>120次/分钟）。
结论
在健康志愿者中，剂量率至少达到48 nmol·min⁻¹·kg⁻¹时，克立夫定耐受性良好且安全。在较宽的剂量范围内，药代动力学呈线性。克立夫定是一种高清除率药物，半衰期极短。克立夫定对血压的影响较小，这可能是由于该健康志愿者群体中存在代偿性压力反射激活。一个简单的Emax模型足以描述药效学反应（MAP/HR）与克立夫定血药浓度之间的关系。
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