Rodríguez Carlos A, Azie Nkechi E, Adams Gregory, Donaldson Kirsteen, Francom Steven F, Staton Brian A, Bombardt Paul A
Clinical Pharmacology, Pharmacia Corporation, Kalamazoo, MI 49007, USA.
J Clin Pharmacol. 2004 Mar;44(3):276-83. doi: 10.1177/0091270003262792.
The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.
对PNU-96391（一种具有中枢多巴胺能功能调节特性的口服活性弱多巴胺D2受体拮抗剂）的安全性、耐受性和药代动力学进行了表征。五十三名健康正常志愿者参与了这项随机、双盲、安慰剂对照的单剂量研究。受试者被分配接受单剂量口服安慰剂以及1、3、10、30、100、150和200 mg的PNU-96391。使用遥测、动态心电图监测、体表心电图、生命体征、安全实验室检查和不良事件报告来评估安全性和耐受性。药代动力学参数通过非模型依赖技术确定。不良事件不常见，强度为轻度至中度，且发生在1至150 mg的剂量范围内。由于严重恶心、头晕、眩晕和心动过速，剂量递增在200 mg时停止。除心率增加外，未观察到对生命体征的其他药物相关影响。安全实验室检查结果无显著变化。血清催乳素的剂量依赖性升高证明了药物活性。PNU-96391吸收迅速，所有受试者在0.5至4小时内达到最大浓度。药物半衰期较短（2至6小时）。主要代谢产物PNU-100014迅速形成，t(max)为1至6小时。代谢产物的峰值水平约为母体药物的一半，半衰期略长（4至10小时）。剂量增加导致PNU-96391和PNU-100014的暴露呈线性增加。因此，PNU-96391在1至150 mg的剂量范围内耐受性良好。
