Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers
Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers
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DOI：
10.1128/aac.50.1.279-285.2006
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发表时间：
2006-01-01
影响因子：
4.9
通讯作者：
Beglinger, C
中科院分区：
文献类型：
--
作者：
Schmitt-Hoffmann, A;Roos, B;Beglinger, C
BAL 8557是一种新型抗真菌三唑类药物BAL 4815的水溶性前药。BAL 4815对广谱的主要机会性和致病性真菌具有活性，包括对其他唑类耐药的菌株。健康男性受试者队列接受单次递增口服（p.o.）BAL 8557剂量相当于100、200或400 mg BAL 4815或单次递增、1 h恒速静脉（i. v.）输注BAL 8557，其相当于50、100或200 mg BAL 4815。在每个队列中，6例受试者被随机分配接受活性药物，2例受试者被分配接受安慰剂。所有剂量均耐受良好，未发生重度或严重不良事件。在p.o.后1.5至3 h观察到BAL 4815的最大血浆浓度。药物摄入或1小时输注结束时。两种给药途径后，观察到的血浆最大药物浓度值和浓度-时间曲线下面积的增加略高于给药剂量的比例。平均消除半衰期特别长（p.o.给药后76至104小时）。分布容积较大（p.o.后155 - 292 L）。给药后为304至494升），全身清除率较低（口服给药后为1.9至2.8升/小时）。静脉内给药后为2.8至5.0升/小时）。BAL 4815的尿液回收率小于输注剂量的0.4%。基于暴露数据，假定BAL 4815的口服生物利用度非常高。BAL 4815的药代动力学非常适合在体内长时间维持BAL 4815的浓度，并能够有效治疗全身性真菌病。
BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.