College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
Zavante Therapeutics, Inc., San Diego, California, USA.
Antimicrob Agents Chemother. 2017 Aug 24;61(9). doi: 10.1128/AAC.00775-17. Print 2017 Sep.
The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters ± standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (), 44.3 ± 7.6 and 370 ± 61.9 μg/ml; time to maximum concentration of drug in serum (), 1.1 ± 0.05 and 1.08 ± 0.01 h; volume of distribution (), 29.7 ± 5.7 and 31.5 ± 10.4 liters; clearance (CL), 8.7 ± 1.7 and 7.8 ± 1.4 liters/h; renal clearance (CL), 6.6 ± 1.9 and 6.3 ± 1.6 liters/h; area under the concentration-time curve from 0 to infinity (AUC), 120 ± 28.5 and 1,060 ± 192 μg·h/ml; and half-life (), 2.4 ± 0.4 and 2.8 ± 0.6 h. After oral administration, the parameters were the following: , 26.8 ± 6.4 μg/ml; , 2.25 ± 0.4 h; /F, 204 ± 70.7 liters; CL/F, 17 ± 4.7 liters/h; CL, 6.5 ± 1.8 liters/h; AUC, 191 ± 57.6 μg · h/ml; and , 9.04 ± 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.
在 28 名健康成年受试者中，单次给予单剂量静脉（i.v.）磷霉素二钠（ZTI-01）和口服磷霉素氨丁三醇后，评估了其药代动力学、安全性和耐受性。受试者在一项 I 期、随机、开放标签、三周期交叉研究中，分别接受了 1 小时静脉输注 1 g 和 8 g 磷霉素二钠和单次口服 3 g 磷霉素氨丁三醇。在给药前和给药后长达 48 小时采集了连续的血样和尿样。静脉注射 1 g 和 8 g 后，磷霉素在血浆中的平均药代动力学参数±标准偏差如下：血清中药物的最大清除率（），44.3±7.6 和 370±61.9μg/ml；血清中药物的最大浓度时间（），1.1±0.05 和 1.08±0.01 h；分布容积（），29.7±5.7 和 31.5±10.4 升；清除率（CL），8.7±1.7 和 7.8±1.4 升/小时；肾清除率（CL），6.6±1.9 和 6.3±1.6 升/小时；从 0 到无穷大的浓度-时间曲线下面积（AUC），120±28.5 和 1,060±192μg·h/ml；半衰期（），2.4±0.4 和 2.8±0.6 h。口服后，参数如下：，26.8±6.4μg/ml；，2.25±0.4 h；/F，204±70.7 升；CL/F，17±4.7 升/小时；CL，6.5±1.8 升/小时；AUC，191±57.6μg·h/ml；和，9.04±4.5 h。与 1 g 静脉剂量相比，口服磷霉素的相对生物利用度为 52.8%。与口服给药相比，静脉给予 1 g 和 8 g 剂量的大约 74%和 80%在 48 小时内以原形排泄到尿液中，而大多数在 12 小时内排泄，与剂量形式无关。在这项研究中没有发现新的安全问题。这项研究的结果支持进一步研究目标患者人群中的静脉内磷霉素，包括患有复杂性尿路感染和肾盂肾炎的患者。
