Schmitt-Hoffmann Anne, Roos Brigitte, Schleimer Michael, Sauer Jill, Man Anthony, Nashed Norman, Brown Thomas, Perez Antonio, Weidekamm Erhard, Kovács Péter
Basilea Pharmaceutica Ltd., P.O. Box 3255, Basel 4002, Switzerland.
Antimicrob Agents Chemother. 2004 Jul;48(7):2570-5. doi: 10.1128/AAC.48.7.2570-2575.2004.
BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. We investigated the safety and pharmacokinetics of BAL5788 in a double-blind, single-ascending-dose study with 40 healthy male subjects. The subjects were randomized to receive placebo (n = 2 subjects per dose) or BAL5788 (n = 6 subjects per dose) as a 200-ml intravenous infusion over 30 min. The BAL5788 doses used were 125, 250, 500, 750, and 1,000 mg (BAL9141 equivalents). All doses were well tolerated, with no severe or serious adverse events (AEs). The most frequent AE was taste disturbance. No electrocardiographic abnormalities and no trends or clinically significant changes in laboratory parameters or vital signs were observed. The maximum concentration of drug in serum and the area under the concentration-time curve for BAL9141 were dose proportional over the dosing range. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment, and the rate of renal clearance of free drug corresponded to the normal glomerular filtration rate for adults. More than 70% of the administered dose was excreted as BAL9141 in the urine, and almost no prodrug was detected. After the infusion of 750 mg, the mean plasma BAL9141 concentrations exceeded the MIC at which 100% of MRSA isolates are inhibited (4 microg/ml) for approximately 7 h, or 58% of a 12-h dosing interval. These results indicate that infusions of 750 mg twice a day should be adequate for the treatment of infections caused by MRSA.
BAL5788是BAL9141的水溶性前药，BAL9141是一种新型广谱头孢菌素，对耐甲氧西林金黄色葡萄球菌（MRSA）和耐青霉素肺炎链球菌具有强大的杀菌活性。我们在一项有40名健康男性受试者参与的双盲、单剂量递增研究中，对BAL5788的安全性和药代动力学进行了研究。受试者被随机分组，接受安慰剂（每剂量2名受试者）或BAL5788（每剂量6名受试者），通过30分钟静脉输注200毫升。使用的BAL5788剂量分别为125、250、500、750和1000毫克（相当于BAL9141的量）。所有剂量耐受性良好，未出现严重不良事件（AE）。最常见的AE是味觉障碍。未观察到心电图异常，实验室参数或生命体征也未出现趋势性变化或具有临床意义的改变。血清中药物的最大浓度以及BAL9141的浓度-时间曲线下面积在给药范围内与剂量成正比。BAL9141的消除半衰期约为3小时。稳态分布容积等于成人体细胞外液腔容积，游离药物的肾脏清除率与成人正常肾小球滤过率相当。超过70%的给药剂量以BAL9141形式经尿液排泄，几乎未检测到前药。输注750毫克后，血浆BAL9141的平均浓度超过了能抑制100% MRSA分离株的最低抑菌浓度（4微克/毫升）约7小时，即12小时给药间隔的58%。这些结果表明，每天两次输注750毫克应足以治疗由MRSA引起的感染。
