Safety and pharmacokinetics of single doses of (+)-calanolide A, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects
Safety and pharmacokinetics of single doses of (+)-calanolide A, a novel, naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy, human immunodeficiency virus-negative human subjects
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DOI：
10.1128/aac.45.5.1379-1386.2001
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发表时间：
2001-05-01
影响因子：
4.9
通讯作者：
Xu, ZQ
中科院分区：
文献类型：
--
作者：
Creagh, T;Ruckle, JL;Xu, ZQ
（+）-Calanolide A是一种新型的，天然存在的人类免疫缺陷病毒1型（HIV-1）逆转录酶的非核苷类抑制剂，首次从马来西亚雨林的热带树木（Calophyllum lanigerum）中分离出来。先前的研究表明(+)-calanolide A对HIV-1逆转录酶具有特异性活性，并且在动物中具有良好的安全性，此外，(+)-calanolide A在体外表现出独特的HIV-1抗性。在健康的hiv阴性志愿者中，对(+)-calanolide A的安全性和药代动力学进行了四个连续的单剂量队列（200,400,600和800 mg）研究。在最初的I期研究中，(+)-calanolide A对47名受试者的毒性最小。头晕、味觉变态、头痛、呕吐和恶心是最常见的不良反应。这些事件并不都被认为与研究用药有关，也与剂量无关。虽然51%的受试者报告轻微和短暂的头晕，但在许多情况下，这似乎与静脉切开术暂时有关。终末半衰期（t(1/2)）的计算由于200、400和600 mg剂量组的受试者内部变异性而被排除，但800 mg剂量组约为20小时。（+）-Calanolide A在给药后迅速吸收，根据剂量的不同，在给药后2.4至5.2 h之间达到血浆中最大药物浓度（T…）值的时间。在所有给药水平下，(+)-calanolide A的血浆水平变化很大；然而，血浆中平均浓度（C…）和血浆浓度-时间曲线下面积均随剂量成比例增加。尽管女性血浆中原始药物水平高于男性，但当剂量按体重标准化时，其药代动力学特征与男性观察到的几乎相同。一般来说，人血浆中(+)-calanolide A的水平高于动物研究预测的水平，但其安全性仍然是良性的。总之，本研究证明了单剂量(+)-calanolide A在健康的hiv阴性个体中的安全性和良好的药代动力学特征。
(+)-Calanolide A is a novel, naturally occurring, nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase first isolated from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Previous studies have demonstrated that (+)-calanolide A has specific activity against the reverse transcriptase of HIV-1 and a favorable safety profile in animals, In addition, (+)-calanolide A exhibits a unique HIV-1 resistance profile in vitro. The safety and pharmacokinetics of (+)-calanolide A was examined in four successive single-dose cohorts (200, 400, 600, and 800 mg) in healthy, HIV-negative volunteers. In this initial phase I study, the toxicity of (+)-calanolide A was minimal in the 47 subjects treated. Dizziness, taste perversion, headache, eructation, and nausea were the most frequently reported adverse events. These events were not all judged to be related to study medication nor were they dose related. While 51% of subjects reported mild and transient dizziness, in many cases this appeared to be temporally related to phlebotomy. Calculation of the terminal-phase half-life (t(1/2)) was precluded by intrasubject variability in the 200-, 400-, and 600-mg dose cohorts but was approximately 20 h for the 800-mg dose group. (+)-Calanolide A was rapidly absorbed following administration, with time to maximum concentration of drug in plasma (T,,,) values occurring between 2.4 and 5.2 h postdosing depending on the dose. Plasma levels of (+)-calanolide A at all dosing levels were quite variable; however, both the mean concentration in plasma (C,,,), and the area under the plasma concentration-time curve increased proportionately in relation to the dose. Although raw plasma drug levels were higher in women than in men, when doses were normalized for body mass, the pharmacokinetic profiles were virtually identical with those observed for males. In general, levels of (+)-calanolide A in human plasma were higher than would have been predicted from animal studies, yet the safety profile remained benign. In conclusion, this study demonstrated the safety and favorable pharmacokinetic profile of single doses of (+)-calanolide A in healthy, HIV-negative individuals.